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Synthesis and Structure-Activity Relationships of Antimalarial 4-oxo-3-carboxyl quinolones
Abstract
Malaria is endemic in tropical and subtropical regions of Africa, Asia, and the Americas. The increasing prevalence of multi-drug-resistant Plasmodium falciparum drives the ongoing need for the development of new antimalarial drugs. In this light, novel scaffolds to which the parasite has not been exposed are of particular interest. Recently, workers at the Swiss Tropical Institute discovered two novel 4-oxo-3-carboxyl quinolones active against the intra-erythrocytic stages of P. falciparum while carrying out rationally directed low-throughput screening of potential antimalarial agents as part of an effort directed by the World Health Organization. Here we report the design, synthesis, and preliminary pharmacologic characterization of a series of analogues of 4-oxo-3-carboxyl quinolones. These studies indicate that the series has good potential for preclinical development.
... By replacing the aromatic groups in the 2 nd ring region of hydroxyquinolone, they obtained effective compounds against malaria in vitro and in vivo [10][11][12]. Next, the antimalarial activity of compounds with 3-carboxyquinolone structure ( Figure 3) and research on this structure led to the effective drug DQ (Decoquinate) ( Figure 6) with remarkable activity on different stages of the parasite [13][14][15][16][17]. ...
... Zhang and his colleagues by derivatizing this compound into analog [10] were obtained by substituting methoxyphenyl in position two in the quinolone ring. This combination IC50 = 0.31 μM against K1 strain (chloroquine resistant strain) and IC50 = 0.10 μM against Plasmodium falciparum strain 3D7 [14]. Dacruz and his colleagues by screening method to the antioxidative drug decoquinate [11]. ...
... The structure of compounds 9-13[13][14][15]26].The special activity of DQ composition on different stages of the parasite is caused by the substitution of groups Aliphatic ethers in the 6 th and 7 th positions of the 3-carboxyquinolone ring are known. Despite all these advantages mentioned for this compound, its weak water solubility and fast metabolism are among its disadvantages. ...
Malaria is a problem whose history exceeds the length of human life on earth. This disease is caused by a plasmodium protozoan in red blood cells and is transmitted through the bite of an infected female Anopheles mosquito and causes fever and chills. Many drugs have been mentioned for this disease, but the newest one is artemisinin. According to the statistics of the World Health Organization, malaria is being transmitted in more than 104 countries of the world. Currently, there are many problems to fight this disease and to control and eliminate it, one of the most important of which is the resistance of the parasite to the malaria drugs available in the market. Therefore, it is necessary to find an alternative drug with a new structure and a different mechanism of action. For this reason, scientists and researchers have focused on heterocyclic rings. With the aim of finding new drugs with a different mechanism of action compared to existing drugs. to synthesize various derivatives and investigate their antimalarial activities on different stages of parasite growth. Meanwhile, the compounds with quinolone ring with different substitutions in different positions of the ring showed a good effect on the blood, liver and sexual stages of the parasite. Therefore, considering the affinity of these compounds on the different growth stages of the malaria parasite as a guide combination for Finding new antimalarial drugs with different mechanism of action were further evaluated and investigated. In this review article, considering the importance of this issue, we introduced some quinolone derivatives with antimalarial effect.
... Many representatives in this chemical class have been studied over the years and have shown an attractive antimalarial profile, especially endochin derivatives with substitutions at the 3-position of the 4(1H)-quinolone including ELQ-300 [15,16] and the 3-carboxyl quinolone derivative decoquinate [17] (Fig. 1). These compounds are powerful inhibitors at nanomolar level against the malaria parasite in blood, liver, and transmission stages [18][19][20][21][22]. Conversely, fewer examples of analogs exploring substituents at the 2-position have been reported [22]. ...
... The substitutions focused on the 5-, 6-, and 7-positions of the 4(1H)-quinolone moiety and included groups with different steric volumes, chain length, and polarity. Mostly, the di-substituted analogs (2,6-and 2,7-positions) displayed decreased in vitro inhibitory activity (18)(19)(20)(21)(22)(23)(24)(25) in comparison with the mono-substituted ones (2-position analogs). Of note, there was a 7-and 33-fold drop in the parasite growth inhibition when the 2,6-di-substituted analogs 21 (6-bromine, IC 50 ¼ 1.5 μM) and 22 (6-pyridine, IC 50 ¼ 7 μM), respectively, were tested and related to the mono-substituted 2-undecyl analog 4 (IC 50 ¼ 0.21 μM). ...
... Nevertheless, no representative is available as a clinical candidate. The scaffold shows attractive in vitro antiplasmodial activity and safety properties, including potent activity against several life stages of the parasite [15,20,22]. Therefore, the parasitological profiling of representatives of this chemical class is of great interest for the development of new drug candidates. ...
4(1H)-quinolone is an attractive template for antimalarial drug discovery campaigns. Given the current global increase in drug and insecticide resistance, the discovery of new antimalarial drugs is an urgent goal for the fight against malaria. Here, the synthesis and antiplasmodial profiling of a series of 4(1H)-quinolone derivatives are reported. Four compounds showed inhibitory activities in submicromolar range against a panel of sensitive and resistant Plasmodium falciparum strains (IC50s = 0.07 – 0.48 μM) and neither cytotoxic (SI > 210) nor hemolytic activities were observed. Representative compounds of the series showed slow-acting in vitro inhibition, enhanced inhibitory activities over the later erythrocytic forms of the parasite, and submicromolar activity against the ookinete stage (IC50ook = 0.7 μM). Evaluation of the mechanism of action indicated that the frontrunner, compound 4 (LSPN182), is a potent (IC50Pfbc1 = 0.5 μM) and selective (SI > 120) inhibitor for the cytochrome bc1 complex of P. falciparum. Moreover, the frontrunner exhibited considerable activity against clinical field isolates of both P. falciparum and P. vivax (IC50s of 0.5 and 1.5 μM, respectively), a noticeable synergic inhibitory behavior when combined with the antimalarial proguanil (FICindex < 1), and modest oral efficacy at 50 mg/kg in a mouse model of P. berghei malaria (45% reduction in parasitemia on day 7 postinfection). Hence, the 4(1H)-quinolone derivatives are attractive chemotypes endowed with relevant in vitro, ex vivo, and in vivo activity.
... i. Solubility assay. The solubility assay [27,28] was carried out on a Biomek FX lab automation workstation (Beckman Coulter, Inc.) using μSOL Evolution software (pION, Inc.) as follows: 10 μL of compound stock was added to 190 μL of 1-propanol to make a reference stock plate. Next, 5 μL of this reference stock plate was mixed with 70 μL of 1-propanol and 75 μL of PBS (pH 7.4) to make the reference plate, and the UV spectrum (250-500 nm) of the reference plate was read. ...
... ii. Parallel artificial membrane permeability assay (PAMPA). A parallel artificial membrane permeability assay (PAMPA) [28,29] was conducted on a Biomek FX lab automation workstation (Beckman Coulter, Inc.) with PAMPA evolution 96 command software (pION Inc.) as follows: 3 μL of 10 mM test compound stock was mixed with 600 μL of PBS (pH 7.4) to make diluted test compound. Then 150 μL of diluted test compound was transferred to a UV plate (pION Inc.), and the UV spectrum was read as the reference plate. ...
Development of resistance against current antimalarial drugs necessitates the search for novel drugs that interact with different targets and have distinct mechanisms of action. Malaria parasites depend upon high levels of glucose uptake followed by inefficient metabolic utilization via the glycolytic pathway, and the Plasmodium falciparum hexose transporter PfHT, which mediates uptake of glucose, has thus been recognized as a promising drug target. This transporter is highly divergent from mammalian hexose transporters, and it appears to be a permease that is essential for parasite viability in intra-erythrocytic, mosquito, and liver stages of the parasite life cycle. An assay was developed that is appropriate for high throughput screening against PfHT based upon heterologous expression of PfHT in Leishmania mexicana parasites that are null mutants for their endogenous hexose transporters. Screening of two focused libraries of antimalarial compounds identified two such compounds that are high potency selective inhibitors of PfHT compared to human GLUT1. Additionally, 7 other compounds were identified that are lower potency and lower specificity PfHT inhibitors but might nonetheless serve as starting points for identification of analogs with more selective properties. These results further support the potential of PfHT as a novel drug target.
... The quinolones with an ethyl carboxylate at the 3 position, a 7-methoxy group preferred over a 5-methoxy group, and an aryl ring at the C-2 position were thought to be the most promising functionalities for antimalarial potency in terms of structure-property interactions. In light of this, compound 22 (ethyl 7-methoxy-2-(3-methoxyphenyl)-4oxo-1,4-dihydroquinoline-3-carboxylate) was determined to be most effective with EC 50 value of 0.13 ± 0.01 μM against the K1 strain of parasite P. falciparum [96]. In accordance with ongoing compilation, endochin-like quinolones (3diaryl ether substituted 4(1H)-quinolones) were made using a unique chemical process, and their efficacy against mouse malaria infections and multidrug-resistant strains of Plasmodium falciparum was tested in vitro by Nilsen et al. [97]. ...
Prevalence of microbial infections and new rising pathogens are signified as causative agent for variety of serious and lethal health crisis in past years. Despite medical advances, bacterial and fungal infections continue to be a rising problem in the health care system. As more bacteria develop resistance to antibiotics used in therapy, and as more invasive microbial species develop resistance to conventional antimicrobial drugs. Relevant published publications from the last two decades, up to 2024, were systematically retrieved from the MEDLINE/PubMed, SCOPUS, EMBASE, and WOS databases using keywords such as quinolones, anti-infective, antibacterial, antimicrobial resistance and patents on quinolone derivatives. With an approach of considerable interest towards novel heterocyclic derivatives as novel anti-infective agents, researchers have explored these as essential tools in vistas of drug design and development. Among heterocycles, quinolones have been regarded extremely essential for the development of novel derivatives, even able to tackle the associated resistance issues. The quinolone scaffold with its bicyclic structure and specific functional groups such as the carbonyl and acidic groups, is indeed considered a valuable functionalities for further lead generation and optimization in drug discovery. Besides, the substitution at N-1, C-3 and C-7 positions also subjected to be having a significant role in anti-infective potential. In this article, we intend to highlight recent quinolone derivatives based on the SAR approach and anti-infective potential such as antibacterial, antifungal, antimalarial, antitubercular, antitrypanosomal and antiviral activities. Moreover, some recent patents granted on quinolone-containing derivatives as anti-infective agents have also been highlighted in tabular form. Due consideration of this, future research in this scaffold is expected to be useful for aspiring scientists to get pharmacologically significant leads.
Graphical abstract
Several Quinolone derivatives based on the SAR approach as potent antimicrobial agents which combat antimicrobial resistance.
... It is the most prevalent parasitic disease and the most common cause of hospital visitation in Democratic Republic of the Congo 3 . This is explained by the increased resistant of parasite to existing drugs such as Chloroquine and Artemisinin, which largely target the asexual blood stage of Plasmodium falciparum life cycle [3][4][5][6] . Faced to this alarming situation, much scientific research is directed towards the discovery of new antimalarial compounds with other mechanisms of action against Plasmodium falciparum and that will be active in multiple stage of life cycle of the latter. ...
... Synthesis of the quinolone ring was accomplished via the Gould-Jacobs reaction; where in the first step substituted anilines 1a,b were condensed with diethyl ethoxymethylenemalonate to provide diethyl 2-((phenylamino)methylene)malonate derivatives 2a,b 22-24 . Gould-Jacobs cyclization of 2a,b in diphenyl ether produced the 4-oxo-1,4-dihydroquinoline-3-carboxylate ethyl esters 3a,b [22][23][24] . The 4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivatives 4a,b were prepared by base hydrolysis of their ester analogs 3a,b upon reflux with Figure 1. ...
In the current study, we designed and synthesized a series of new quinoline derivatives 10a-p as antiproliferative agents targeting cancer through inhibition of VEGFR-2. Preliminary molecular docking to assess the interactions of the designed derivatives with the binding site of VEGFR-2 (PDB code: 4ASD) displayed binding poses and interactions comparable to sorafenib. The synthesized compounds exhibited VEGFR-2 inhibitory activity with IC50 ranging from 36 nM to 2.23 μM compared to sorafenib (IC50 = 45 nM), where derivative 10i was the most potent. Additionally, the synthesized derivatives were evaluated in vitro for their cytotoxic activity against HepG2 cancer cell line. Seven compounds 10a, 10c, 10d, 10e, 10i, 10n and 10o (IC50 = 4.60, 4.14, 1.07, 0.88, 1.60, 2.88 and 2.76 μM respectively) displayed better antiproliferative activity than sorafenib (IC50 = 8.38 μM). Compound 10i was tested against Transformed Human Liver Epithelial-2 normal cell line (THLE-2) to evaluate its selective cytotoxicity. Furthermore, 10i, as a potent representative of the series, was assayed for its apoptotic activity and cell cycle kinetics’ influence on HepG2, its effects on the gene expression of VEGFR-2, and protein expression of the apoptotic markers Caspase-7 and Bax. Compound 10i proved to have a potential role in apoptosis by causing significant increase in the early and late apoptotic quartiles, a remarkable activity in elevating the relative protein expression of Bax and Caspase-7 and a significant reduction of VEGFR-2 gene expression. Collectively, the obtained results indicate that compound 10i has a promising potential as a lead compound for the development of new anticancer agents.
... In general, compound 173b exhibited the best balance between potency, physicochemical properties, in vitro mouse liver microsome stability, in vivo pharmacokinetic prole, and the best efficacy, which was equivalent to that of amodiaquine, so 173b is promising for further development as antimalarials. 77 Winter et al. synthesized endochin-like quinolones 174, and half of the derivatives exhibited promising antiplasmodial activities with IC 50 values ranging from 0.02 to around 30 nM against CQS D6, MDR Dd2, and TM90-C2B P. falciparum strains. Compound 174a (IC50: 0.02 nM) was found to be most active against CQSD6 and MDRDd2, which was 15-320 fold more potent than the references, chloroquine, artemisinin, and atovaquone (IC50: 6.4, 0.81 and 0.3 nM, respectively) against CQS 3D7, and 25-5650 times more active than the three references (IC50: 113, 0.6 and 0.5 nM, respectively) against MDR Dd2. ...
4-Quinolone and its analogs are heterocyclic classes of organic compounds displaying biologically active and a broad spectrum of pharmaceutical drug scaffolds. 4-Quinolone is the first-line chemotherapeutic treatment for a wide spectrum of bacterial infections. Recently, 4-quinolone and its derivatives have been shown to have the potential to cure and regulate various acute and chronic diseases, including pain, ischemia, immunomodulation, inflammation, malarial, bacterial infection, fungal infection, HIV, and cancer, based on several reports. This review highlights and provides brief information to better understand the development of experimental progress made to date in the synthetic protocol towards 4-quinolone and its analogs. Thus, classical synthesis protocol, metal-free reaction protocol, and transition metal-catalyzed reaction procedures are briefly discussed along with the pharmaceutical activities of selected 4-quinolone derivatives.
... In general, compound 173b exhibited the best balance between potency, physicochemical properties, in vitro mouse liver microsome stability, in vivo pharmacokinetic prole, and the best efficacy, which was equivalent to that of amodiaquine, so 173b is promising for further development as antimalarials. 77 Winter et al. synthesized endochin-like quinolones 174, and half of the derivatives exhibited promising antiplasmodial activities with IC 50 values ranging from 0.02 to around 30 nM against CQS D6, MDR Dd2, and TM90-C2B P. falciparum strains. Compound 174a (IC50: 0.02 nM) was found to be most active against CQSD6 and MDRDd2, which was 15-320 fold more potent than the references, chloroquine, artemisinin, and atovaquone (IC50: 6.4, 0.81 and 0.3 nM, respectively) against CQS 3D7, and 25-5650 times more active than the three references (IC50: 113, 0.6 and 0.5 nM, respectively) against MDR Dd2. ...
Quinolone and its analogs are heterocyclic classes of organic compounds displaying biologically active and a broad spectrum of pharmaceutical drug scaffolds. 4-Quinolone is the first-line chemotherapeutic treatment for a wide spectrum of bacterial infections. Recently, 4-quinolone and its derivatives have been shown to have the potential to cure and regulate various acute and chronic diseases, including pain, ischemia, immunomodulation, inflammation, malarial, bacterial infection, fungal infection, HIV, and cancer, based on several reports. This review highlights and provides brief information to better understand the development of experimental progress made to date in the synthetic protocol towards 4-quinolone and its analogs. Thus, classical synthesis protocol, metal-free reaction protocol, and transition metal-catalyzed reaction procedures are briefly discussed along with the pharmaceutical activities of selected 4-quinolone derivatives.
... Para substituted phenyl rings either decreased activity by four-fold or completely, in addition to significant decrease in aqueous solubility. Meta substituted rings observed the best potency with acceptable aqueous solubility and increased permeability (Figure 13) [56]. ...
Malaria is a global public health issue. Despite the efforts in malaria prevention, nearly half the world’s population is at risk of infection. Until present-day, researchers are struggling to design and discover an efficacious antimalarial. In comparison to most common antimalarial chemotypes that eliminate erythrocytic stages of P. falciparum, 4(1H)-quinolones and 4(1H)-pyridones exhibit antimalarial activity against multiple stages of the parasite. They have potential to treat blood stages of multidrug resistant P. falciparum malaria, eradicate dormant exoerythro stages of relapsing malaria species (P. vivax), and prevent transmission of infectious gametocytes to mosquitoes. However, thus far, the advancement of these chemotypes towards pre-clinical and clinical development has been impeded due to poor physicochemical properties, poor oral bioavailability, and poor dose-proportionality limiting preclinical safety and toxicity studies. Despite all these challenges, 4(1H)-quinolones and 4(1H)-pyridones continue to be at the forefront for the development of the next-generation antimalarials as they would have tremendous global public health impact and could significantly enhance current malaria elimination efforts.
... In addition, other carboxyquinolones were prepared and tested as potential antimalarials, and TDR 42098 (42) showed IC 50 = 0.10 CM against P. falciparum 3D7 and IC 50 = 0.13 CM against strain K1 [123]. The most potent compound decoquinate (43) demonstrated IC 50 = 0.003 CM against P. falciparum liver stage, IC 50 = 0.036 CM against blood stage and IC 50 = 0.036 CM against sexual stage of the malaria parasite; moreover it was approved as a veterinary drug [124]. ...
Background: Despite the successes achieved recently in the treatment of various infectious diseases, the morbidity and mortality associated with malaria remain major burdens. Objective: The main limitations of conventional malaria therapy are the development of multi-drug resistance resulting in high dosage of different drugs and subsequent pill burden and toxicity. Thus, new effective antimalarial agents are urgently needed due to the increasing drug resistance of Plasmodium sp. Discussion: Nature is successful in providing mankind with compounds against infectious diseases. Many of small drugs on the market were originally developed from natural-based compounds. Scaffolds, such as monoor diazanaphthalenes, naphthoquinone, indole, pyrrole or endoperoxides can be considered as privileged structures for the discovery of new antimalarials. Nevertheless, some difficulties associated with natural lead compounds derived from these scaffolds, such as their synthesis, limited aqueous solubility, chemical or metabolic instability and wide spectrum of biological effects are needed to be solved. Conclusion: Thus, semisynthetic or synthetic analogues of natural antimalarial agents exhibiting optimized physicochemical properties, more selective biological activity and/or higher potency especially against resistant or multidrug resistant strains have been designed. The review is focused on selected recently reported potential antimalarial agents derived from isolated bioactive natural compounds based on the above-mentioned scaffolds. Their mechanism of action and structure-activity relationships are briefly mentioned.
... Since the discovery of the anti-malarial activity of ICI56-780, a carboxyl derivative of quinolones [85], screening of new compounds has led to the discovery of various 3-carboxyquinolones, which displayed in vitro activity <100 nM against P. falciparum strains and targeted the cytochrome bc 1 complex and the dihydroorotate dehydrogenase (DHODH) [86,87]. ...
Malaria, a parasite vector-borne disease, is one of the most significant health threats in tropical regions, despite the availability of individual chemoprophylaxis. Malaria chemoprophylaxis and chemotherapy remain a major area of research, and new drug molecules are constantly being developed before drug-resistant parasites strains emerge. The use of anti-malarial drugs is challenged by contra-indications, the level of resistance of Plasmodium falciparum in endemic areas, clinical tolerance and financial cost. New therapeutic approaches are currently needed to fight against this disease. Some antibiotics that have shown potential effects on malaria parasite have been recently studied in vitro or in vivo intensively. Two families, tetracyclines and macrolides and their derivatives have been particularly studied in recent years. However, other less well-known have been tested or are being used for malaria treatment. Some of these belong to older families, such as quinolones, co-trimoxazole or fusidic acid, while others are new drug molecules such as tigecycline. These emerging antibiotics could be used to prevent malaria in the future. In this review, the authors overview the use of antibiotics for malaria treatment.
... 20 Studies by Manetsch, Kyle, Guy, Ward and O'Neill have shown that considerable optimization can be done to offset some of the liabilities of the 4(1H)-quinolone compound class. [22][23][24][25] However, these failed to address the fundamental questions about why 6b has such broad range anti-malarial activity or how structural modifications of 6b may reduce the propensity to induce resistance. Given the promise of this scaffold, detailed structure-activity relationship studies against the blood and liver stages of the parasite were conducted in order to gain a deeper understanding of this promising scaffold. ...
Though malaria mortality rates are down 48% globally since 2000, reported occurrences of resistance against current therapeutics threaten to reverse that progress. Recently, antimalarials which were once considered unsuitable therapeutic agents have been revisited to improve physicochemical properties and efficacy required for selection as a drug candidate. One such compound is 4(1H)-quinolone ICI 56,780, which is known to be a causal prophylactic that also displays blood schizonticidal activity against P. berghei. Rapid induction of parasite resistance however, stalled its further development. We have completed a full structure-activity relationship study on 4(1H)-quinolones, focusing on the reduction of cross-resistance with atovaquone for activity against the clinical isolates W2 and TM90-C2B, as well as the improvement of microsomal stability. These studies revealed several frontrunner compounds with superb in vivo antimalarial activity. The best compounds were found to be curative with all mice surviving a Plasmodium berghei infection after 30 days.
... A number of biological activities have been associated with quinoline-containing compounds such as anti-inflammatory 2 , antiallergic 3 , antimalarial 4 , antibacterial 5 , antiproliferative 6 , anticancer 7 and antiparasitic 8 activities. In the last few years, much work has been contributed in the field of quinolinones, with the aim to investigate and compare their anticancer activity 9 . The 4(1H) quinolone structure plays an extremely an important role in the field of pharmaceutical chemistry. ...
In the present work, a series of novel Schiff's bases of 2-Quinolones were synthesized and characterized. The synthesized compounds were screened for their antibacterial activity against different bacterial strains. Out of the 15 compounds screene d for the antibacterial activity,3 compounds (JMB3, JMB11, JMB13) showed antibacterial activity against Pseudomonas aeruginosa and Escherichia coli and were comparable with the standard.
... Derivatization of TDR 42098 (26, Figure 6) produced the analogue (27, Figure 7) bearing a metasubstituted aromatic ring at C-2. This derivative has midrange EC 50 values of 0.13 μM and 0.10 μM against the K1 and 3D7 strains of P. falciparum, respectively [44]. ...
Available anti-malarial tools have over the ten-year period, 2002 to 2012, dramatically reduced the number of fatalities attributed to malaria, from one million to less than six-hundred and thirty thousand. Although fewer people recently die from malaria, emerging resistance to the first-line anti-malarial drugs, namely artemisinins in combination with quinolines and arylmethanols, necessitates the urgent development of new anti-malarial drugs to curb the disease. The quinolones remain a promising class of compounds, with some demonstrating strong in vitro activity against the malaria parasite. This review presents the progress made in the development of potential anti-malarial quinolones, since 2008. The efficacy of these compounds against both asexual blood stages and other stages of the malaria parasite, the nature of putative targets, and a comparison of these properties with anti-malarial drugs currently in clinical use, are discussed.
... A systematic approach including a methodical variation of sterics, electrostatics and hydrophobics following Topliss and Hansch analysis was applied to conduct the optimization. A meta-substituted aryl group at the C2 position was established to be extremely important for antimalarial activity [57]. In order to investigate this trend more precisely, more than 20 additional analogues were synthesized and tested in vitro ( Figure 12). ...
Infectious diseases are the second leading cause of deaths in the world with malaria being responsible for approximately the same amount of deaths as cancer in 2012. Despite the success in malaria prevention and control measures decreasing the disease mortality rate by 45% since 2000, the development of single-dose therapeutics with radical cure potential is required to completely eradicate this deadly condition. Targeting multiple stages of the malaria parasite is becoming a primary requirement for new candidates in antimalarial drug discovery and development. Recently, 4(1H)-pyridone, 4(1H)-quinolone, 1,2,3,4-tetrahydroacridone, and phenoxyethoxy-4(1H)-quinolone chemotypes have been shown to be antimalarials with blood stage activity, liver stage activity, and transmission blocking activity. Advancements in structure-activity relationship and structure-property relationship studies, biological evaluation in vitro and in vivo, as well as pharmacokinetics of the 4(1H)-pyridone and 4(1H)-quinolone chemotypes will be discussed.
... Concentration of both organic layers found them to be impure, so they were combined, concentrated, and further purified by FCC (eluent MeOH/EtOAc/PE 0:50:50 to 0:100:0, then up to 2:98:0) to give 1.213 g of brown solid (35%). 1 Ethyl 5-Methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (2e). 37 Ethyl 8-chloro-5-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (2d) (500 mg, 1.78 mmol) was dispersed in EtOH (10 mL) before sonication to degas the solvent. The vessel was evacuated and filled with nitrogen before addition of 10% Pd/C (50 mg), with care. ...
Established therapy in Alzheimer's disease centres on potentiation of the endogenous orthosteric ligand, acetylcholine, at the M1 muscarinic receptors found in higher concentrations in the cortical and hippocampal brain regions. Unfortunately, such therapy invariably suffers from undesirable effects, in part due to indiscriminate activation of other members of the muscarinic receptor family. Due to high sequence conservation in the orthosteric binding site across these receptors, to date, development of a truly M1 selective agonist has not been achieved. M1 muscarinic positive allosteric modulators/allosteric agonists such as BQCA offer an attractive solution to this problem, being exquisitely M1 selective over other muscarinic subtypes and exhibiting a saturable effect, thus reducing problems associated with overdosing. A common difficulty with allosteric ligands is interpreting SAR, based on all-encompassing 'allosteric potency' values derived from modulator titration curves established against a fixed concentration of agonist. In reality these potency values are made up of multiple pharmacological parameters - each potentially, and differentially sensitive to structural modification of the ligand. Herein, we report a novel series of BQCA analogues bearing a variety of structural modifications which appear to augment ligand affinity for the receptor (pKB), intrinsic efficacy (τB) and both binding (α) and functional (β) cooperativity with the orthosteric ligand acetylcholine. Ultimately, development of such enriched SAR surrounding allosteric modulators is anticipated to provide a more thorough mechanistic explanation for their mode of action, and ultimately allow tailored allosteric ligands to be developed.
... Our original studies showed that analogs bearing a 7-methoxy group on the benzenoid ring generally had more antimalarial activity than compounds with a 5-methoxy substituent. 12 This suggested that the substitution pattern of the benzenoid ring was another feature important for antimalarial potency. A series of compounds 9-20, varying substituents on the benzenoid ring while holding constant the meta-substituted phenyl ring at the 2-position was prepared and tested (Table 2). ...
Malaria is a protozoal parasitic disease that is widespread in tropical and subtropical regions of Africa, Asia, and the Americas and causes more than 800,000 deaths per year. The continuing emergence of multidrug-resistant Plasmodium falciparum drives the ongoing need for the development of new and effective antimalarial drugs. Our previous work has explored the preliminary structural optimization of 4(1H)-quinolone ester derivatives, a new series of antimalarials related to the endochins. Herein, we report the lead optimization of 4(1H)-quinolones with a focus on improving both antimalarial potency and bioavailability. These studies led to the development of orally efficacious antimalarials including quinolone analogue 20g, a promising candidate for further optimization.
... 1,13 A related set of 4-oxo-3-carboxyl analogues (6) were recently developed by using a parallel approach of SAR and pharmacologic characterization to design quinolones that were less prone to cross-resistance with atovaquone. 12 Given the sparse number of chemotypes with proven antirelapse activity, we have explored the 7-(2-phenoxyethoxy)-4(1H)-quinolones (PEQs) scaffold to optimize SPR and blood stage antimalarial activity. Since the rapid induction of resistance reported in P. berghei was likely due to cytochrome b mutations, we also optimized the scaffold for potency against clinically relevant atovaquone resistant P. falciparum. ...
ICI 56,780 (5) displayed causal prophylactic and blood schizonticidal activity (ED50=0.05 mg/kg) in rodent malaria models but produced rapid acquisition of parasitological resistance in P. berghei infected mice. Herein we describe the synthesis of analogues of 5 with EC50 as low as 0.15 nM against multidrug resistant P. falciparum. Optimal activity with low cross-resistance indexes (RI) to atovaquone was achieved by introducing ortho-substituted aryl moieties at the 3-position of the 7-(2-phenoxyethoxy)-4(1H)-quinolone core.
Mg‐catalyzed [4+2] cycloaddition reactions between 2‐aminobenzaldehydes and ynones offered an array of 2‐arylquinoline motifs merged with a CF3‐acyl group. Furthermore, with Mg‐catalyzed [4+2] annulation as the key step, DDD107498, DDD102542, and Hit analogues were assembled. Finally, a computational study of the reaction mechanism was conducted.
The review summarizes recent advances in the synthesis of C2‐halogenated nitrogen heterocycles via nucleophilic halogenation of corresponding N‐oxides as well as application of this methodology in the synthesis of pharmaceuticals. Both scientific and patent literature is reviewed mostly over the period of the last ten years. The review contains a practical guide (typical procedures and infographic based on extensive literature analysis), which can help practitioners in choosing optimal reagents/conditions for nucleophilic halogenation of N‐heterocycles of different types. The bibliography contains 199 references.
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A dihydroartemisinin-ciprofloxacin hybrid was synthesized and its antiplasmodial activity was evaluated against the 3D7 strain of Plasmodium falciparum. It was hypothesized that linking the artemisinin pharmacophore (which targets the heme detoxification pathway of the malaria parasite) with the fluoroquinolone scaffold (which targets plasmodial DNA gyrase enzyme) will produce a hybrid antimalarial compound with enhanced potency. The hybrid was synthesized by esterifying the carboxyl group of ciprofloxacin with the hydroxyl group of dihydroartemisinin; it displayed excellent antimalarial activity against the strain of P. falciparum tested with between 3-and 4-fold greater activity (IC 50 : 2.99 nM) compared to the reference drugs chloroquine (IC 50 : 13.003 nM) and dihydroartemisinin alone (IC 50 : 9.968 nM) against the parasite. The synthesized compound was also tested for its in vitro cytotoxicity and it was found to be relatively non-cytotoxic (LC 50 : 50.78 µg/ml) as compared to cyclophosphamide (LC 50 : 1.08 µg/ ml). In silico prediction of the Lipinski properties of the hybrid showed that the compound possesses good drug-like properties. The hybrid demonstrated the good activity with minimal toxicity and is, therefore, a potential candidate for further exploration in the quest for desperately needed new antimalarial drugs.
Methods for the synthesis and the properties of methylamino- and dimethylaminoquinolines, as well as the interactions between their amino groups and the heteroatom of the ring are reviewed. Particular attention is devoted to the recently obtained 4,5-bis(dimethylamino)-quinolines, which are protonated depending on the substituients primarily at the quinoline ring nitrogen atom or at the peridimethylamino groups. In the latter case these compounds can be characterized as proton sponges. A total of 134 literature references are presented.
Malaria remains one of the most deadly infectious diseases globally. Considering the growing spread of resistance, development of new and effective antimalarials remains an urgent priority. Quinolones, which are emerged as one of the most important class of antibiotics in the treatment of various bacterial infections, showed potential in vitro antiplasmodial and in vivo antimalarial activities, making them promising candidates for the chemoprophylaxis and treatment of malaria. This review presents the current progresses and applications of quinolone-based derivatives as potential antimalarials to pave the way for the development of new antimalarials.
Malaria deaths have been decreasing over the last 10-15 years, with global mortality rates having fallen by 47% since 2000. While the World Health Organization (WHO) recommends the use of artemisinin-based combination therapies (ACTs) to combat malaria, the emergence of artemisinin resistant strains underscores the need to develop new antimalarial drugs. Recent in vivo efficacy improvements of the historical antimalarial ICI 56,780 have been reported, however with the poor solubility and rapid development of resistance, this compound requires further optimization. A series of piperazine-containing 4(1H)-quinolones with greatly enhanced solubility were developed utilizing structure-activity relationship (SAR) and structure-property relationship (SPR) studies. Furthermore, promising compounds were chosen for an in vivo scouting assay to narrow selection for testing against a more accurate in vivo Thompson test. Finally, two piperazine-containing 4(1H)-quinolones were curative in the conventional Thompson test and also displayed in vivo activity against the liver stages of the parasite
An efficient and convenient method of C5-selective halogenation of quinoline derivatives was developed. The reaction proceeds smoothly in water with readily available N-halosuccinimides (NCS, NBS and NIS) as the halogenation reagents. This method features metal-free catalysis, no additional oxidants and additives, broad substrate scope and short reaction time.
A mild, rapid and efficient method for copper-catalyzed nitration of quinolines at the C5 or C7 position was reported firstly by using sodium nitrite as the nitro source. A series of nitrated quinoline derivatives were achieved in moderate to good yields via remote C–H activation. The method overcomes some shortcomings reported in previous nitration strategies, such as employing expensive metal catalysts or using toxic and unstable nitrating agents. Furthermore, some of the products can be obtained through filtration which displays the operational simplicity of this methodology. Importantly, this protocol may provide a practical synthetic tool for the introduction of nitro groups into drug molecules.
The 2,6,8-triaryl-3-iodoquinolin-4(1H)-ones derived from the 2,6,8-triarylquinolin-4(1H)-ones were found to undergo Suzuki-Miyaura cross-coupling with arylboronic acids to afford the corresponding 2,3,6,8-tetraarylquinolin-4(1H)-ones. Sonogashira cross-coupling of the 2,6,8-triaryl-3-iodoquinolin-4(1H)-ones with terminal acetylene in DMF-water (4:1, v/v) in the presence of triethylamine, on the other hand, afforded the 2-substituted 4,6,8-triaryl-1H-furo[3,2-c]quinolines in a single-pot operation.
The synthesis of 1,4-dihydro-4-oxoquinoline derivatives (4-quinolones) based on a BSA [N,O-bis(trimethylsilyl)acetamide]-mediated cyclization of substituted 1-(2-methoxyphenyl)-3-(alkyl/arylamino)prop-2-en-1-ones is described. The reaction belongs to a rare set of cyclizations in which a methoxy group serves as the leaving group. Reaction takes place by the action of silylating agent under mild conditions and provides high yields of pure products following simple aqueous work-up. The versatility of the approach is exemplified by a wide range of 1-alkyl/aryl 3-carboxylates and 3-nitriles that have been prepared. A crucial advantage of this approach is the facile availability of starting methoxy compounds enabling new synthetic possibilities as well as improved cost efficiency.
A novel and convenient method has been developed for the regioselective iodination of quinolines at their C3 position under metal-free conditions. Iodinated quinolines, which are popular building blocks in organic and medicinal chemistry, can be prepared in gram quantities and good yields using this method and further derivatized to give increasingly complex compounds. Preliminary mechanistic studies have shown that this reaction most likely occurs via a radical intermediate.
The 3-carboxy-quinolin-4(1H)-ones constitute an important group of antimicrobial agents widely used in treatment of several diseases. The nalidixic acid, the first quinolone derivative developed as antibacterial agent in the early 1960s, was used as prototype to this group improvement. However, these compounds were neglected until the development of fluoroquinolones. The research associated to these antibiotics has been developed since ciprofloxacin was employed in the late 1980s, and from that period on it has been object of study. The versatility of 3-carboxy -quinolin-4(1H)-ones is associated to their wide range of biological activities reported in the literature, such as: antibacterial, antiviral, antiprotozoal, antifungal, and antitumoral. This review gives a highlight to the main synthetic methodologies for the synthesis of these heterocycles: Gould-Jacobs, Grohe-Heitzer, Baylis-Hillman, reactions employing transition metals and solid-phase reactions. Additionally, examples of the influence of chiral substituents on antibacterial activity are presented.
A Transition-metal-free C-3-arylation of quinolin-4-ones in the presence of base has been achieved by using arylhydrazines as aryl radical source and air as oxidant. Reaction proceeds smoothly at room temperature and does not require any prefunctionalization and N-protection of quinoline-4-ones. The utility of this methodology is further demonstrated in synthesis of quinolin-quinolone hybrid as well as 6-aryl-benzofuro[3,2-c]quinoline scaffold.
This review describes the synthesis, biological activities, and tautomerism of various 4-quinolones together with related compounds including 4-oxopyridazino[3,4-b]quinoxalines (bioisostere of 4-quinolones).
A clean arylation protocol of ethyl acetoacetate was developed using hypervalent diaryliodonium salts under mild and metal-free conditions. The scope of the reaction, using symmetric and unsymmetric iodonium salts with varying sterics and electronics was examined. Further, this method has been applied for the synthesis of antimalarial compound ELQ-300, which is currently in preclinical development.
An efficient, two‐step synthetic strategy has been developed to access the quinolone, naphthyridone and benzonaphthyridone classes of chemotherapeutic agents from Baylis–Hillman adducts. The method involves tandem aza‐Michael addition, S N Ar cyclisation followed by oxidation of the resulting 4‐hydroxy‐1,2,3,4‐tetrahydroquinoline or 4‐hydroxy‐1,2,3,4‐tetrahydro‐1,8‐naphthyridine derivative using IBX, and works well with substrates having a wide variety of substitution pattern.
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The use of palladium complexes in catalyzing the cross‐coupling of halogenated quinolines with various organometalic reagents has led to the development of radically new methods of synthesizing novel substituted quinoline derivatives. The focus of this review is on the application of the following palladium‐catalyzed reactions of halogenated quinolines with organometalic reagents to afford substituted quinoline derivatives: Kumada, Stille, Negishi, Sonogashira, Suzuki, Heck, and Hiyama cross‐coupling reactions.
The reaction of the 6‐substituted 1‐methyl‐4‐quinolone‐3‐carboxylates 10a,b with hydrazine hydrate gave the 3‐carbohydrazides 7a,b, respectively, whose reaction with 2‐, 3‐, and 4‐pyridinecarbaldehydes afforded the 3‐(N 2‐pyridylmethylene)carbohydrazides 8a–c and 9a–c. The Curtius rearrangement of compound 7b provided the N,N′‐bis(4‐quinolon‐3‐yl)urea 14 presumably via the 3‐carboazide 11 and then 3‐isocyanate 12. Compounds 7a, 8a, and 9a were found to possess antimalarial activity from the in vitro screening data. J. Heterocyclic Chem.,(2011).
Increasing antibiotic resistance urgently requires novel therapeutic options to combat bacterial infections. The anti-virulence therapy selectively intervening with pathogenicity without affecting bacterial viability is such a strategy to overcome resistance. We consider the virulence regulator PqsR as an attractive target in the human pathogen Pseudomonas aeruginosa, and recently discovered the first PqsR antagonists, which, however, suffered from poor aqueous solubility. In this work, the antagonists were structurally modified to become more soluble, and their structure-activity as well as structure-property relationships were studied. A novel promising compound with improved solubility and enhanced anti-virulence activity was discovered (IC50: 3.8 μM, pyocyanin). Our findings emphasize the crucial role of substituents at the 3-position and the carbonyl group at the 4-position for ligand-receptor interactions, and illuminate the way for further optimization of PqsR antagonists as anti-virulence agents.
The review focuses on the methods of synthesis of 2-(1-alkoxyalkylidene)-1,3-dicarbonyl compounds and their chemical transformations. The reactivity of such compounds toward various mono- and dinucleophilic reagents is considered. The potential of these compounds for synthesis of different acyclic, carbo- and heterocyclic molecules is demonstrated. Special attention is paid to the practical use of 2-(1-alkoxyalkylidene)-1,3-dicarbonyl compounds and their derivatives, which are of interest in medicine and for design of new materials.
A convenient way to introduce aryl functionalization in the 6-position of 4-quinolones is developed via selective bromination and subsequent arylation by Suzuki cross-coupling. Ethyl 4-quinolone 3-carboxylates were subjected to selective bromination at C-6 followed by arylation under microwave irradiation yielded the desired cross-coupling products within 5 minutes. This approach can expediently be used for library synthesis of aryl functionalized 4-quinolone derivative, an important class of biologically active compounds.
Malaria kills approximately 1 million people a year, mainly in sub-Saharan Africa. Essential steps in the life cycle of the
parasite are the development of gametocytes, as well as the formation of oocysts and sporozoites, in the Anopheles mosquito vector. Preventing transmission of malaria through the mosquito is necessary for the control of the disease; nevertheless,
the vast majority of drugs in use act primarily against the blood stages. The study described herein focuses on the assessment
of the transmission-blocking activities of potent antierythrocytic stage agents derived from the 4(1H)-quinolone scaffold. In particular, three 3-alkyl- or 3-phenyl-4(1H)-quinolones (P4Qs), one 7-(2-phenoxyethoxy)-4(1H)-quinolone (PEQ), and one 1,2,3,4-tetrahydroacridin-9(10H)-one (THA) were assessed for their transmission-blocking activity against the mosquito stages of the human malaria parasite
(Plasmodium falciparum) and the rodent parasite (P. berghei). Results showed that all of the experimental compounds reduced or prevented the exflagellation of male gametocytes and,
more importantly, prevented parasite transmission to the mosquito vector. Additionally, treatment with ICI 56,780 reduced
the number of sporozoites that reached the Anopheles salivary glands. These findings suggest that 4(1H)-quinolones, which have activity against the blood stages, can also prevent the transmission of Plasmodium to the mosquito and, hence, are potentially important drug candidates to eradicate malaria.
Malaria represents a significant health issue and effective novel drugs are needed to address parasite resistance to the current drug arsenal. Antimalarial drug discovery has historically benefited from the whole-cell (phenotypic) screening approach to identify lead molecules in the search for new drugs. This approach has been utilized by several groups to optimize older weak antimalarial pharmacophores, such as the quinolone to potent and highly efficacious compounds that poised to enter clinical trials. More recently, GNF/Novartis, GSK and others have employed this same approach in HTS of large compound libraries to find novel scaffolds that have also been optimized to clinical candidates by GNF/Novartis. This perspective outlines some of the inherent challenges in cell-based medicinal chemistry optimization including optimization of oral exposure and hERG activity.
A mild method for the regioselective C2-bromination of fused azine N-oxides is presented, employing tosic anhydride as the activator and tetra-n-butylammonium bromide as the nucleophilic bromide source. The C2-brominated compounds are produced in moderate to excellent yields and with excellent regioselectivity in most cases. The potential extension of this method to other halogens, effecting C2-chlorination with Ts(2)O/TBACl is also presented. Finally, this method could be incorporated into a viable one-pot oxidation/bromination process, using methyltrioxorhenium/urea hydropgen peroxide as the oxidant.
Malaria is one of the most devastating diseases the world has ever known affecting almost 250 million people a year and resulting
in over 860,000 deaths, mostly of children under the age of 5years. With increased funding and the advent of public–private
partnerships such as Medicines for Malaria Venture, the search for new medicines to combat malaria has, over the last decade,
undergone a renaissance. This is both as a result of increased funding and the recent development of new tools, such as high-throughput
screening technology. In addition, public and political attention has been caught by calls from the Gates Foundation and World
Health Organization for a strategy to eradicate malaria once and for all. This will mean having therapeutics to combat not
only Plasmodium falciparum malaria – predominantly found in Africa – but also Plasmodium vivax malaria, which is endemic in many parts of Asia and South America. However, as with all infectious disease, there is a constant
threat of drug resistance, and therefore the continual need for new medicines. In this review, we summarise the challenges
posed by malaria drug discovery and development. We present the pipeline of existing treatments and those in clinical development.
New modes of action are under investigation in preclinical discovery, and we review the opportunities as well as the risks
to these early stage projects.
KeywordsAntimalarial-Eradication-Malaria-
Plasmodium falciparum
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Plasmodium vivax
-Transmission blocking-Whole cell screening
A series of substituted quinolines was prepared from arylamines, aldehydes, and terminal olefins (see scheme). The palladium-catalyzed sequential formation of C-C bonds proceeds smoothly with both electron-deficient and electron-rich olefins. When acrylic acid is used as terminal olefin, decarboxylation occurs to provide 2-substituted quinolines.
The structures of the potentially tautomeric 2-aryl-3-bromoquinolin-4(1H)-ones were studied using spectroscopic (NMR, IR and mass), X-ray crystallographic and computational techniques. These systems are found to exist in solution (1H NMR and 13C NMR) and solid state (IR and X-ray) as the NH-4-oxo derivatives, and their carbonyl nature is also corroborated by comparison of their spectroscopic data with those of the corresponding N-methylated and O-methylated derivatives. The presence of the quinolinol (hydroxyquinoline) isomer in the gas phase is confirmed by low and high resolution mass spectrometry.
WR 243251 is a dihydroacridinedione that was evaluated for antimalarial blood schizonticidal activity in vitro and in vivo.
The in vitro doses calculated to kill 50% of organisms were 11 nM for a chloroquine-susceptible, mefloquine-resistant standard
strain and 25 nM for a chloroquine- and pyrimethamine-resistant standard strain. The total dose needed to cure 100% of mice
infected with a drug-susceptible strain of Plasmodium berghei was 12 to 20 mg/kg of body weight for both oral and subcutaneous
administration. The regimen needed to cure 100% of Aotus monkeys infected with Plasmodium falciparum was 8 mg/kg/day for 3
days (chloroquine-susceptible strain) and 16 mg/kg/day for 3 days (chloroquine-resistant strain). The 100% curative doses
for Aotus monkeys did not increase for parasites previously exposed to subcurative doses. The absolute value of the curative
doses of WR 243251 was comparable to or lower than the values for clinical antimalarial agents. The high absolute activity,
comparability of activities against susceptible and resistant parasites, and inability to induce resistance by exposure to
subcurative doses suggest that WR 243251 has strong potential as a blood schizonticidal agent.
Floxacrine was a promising antimalarial compound that led to the identification of WR 243251. On the basis of their structures, we suspected that these compounds might be good inhibitors of hematin polymerization. Indeed, WR 243251 was as potent and floxacrine was only 2-fold less potent than chloroquine as inhibitors of this process. However, this hematin polymerization inhibition did not completely account for the increased antimalarial potency of WR 243251 versus chloroquine. The WR 243251 ketone hydrolysis product WR 243246 was without activity against hematin polymerization. These data also confirm that hematin polymerization inhibition can be quite sensitive to small changes in inhibitor structure.
Where malaria prospers most, human societies have prospered least. The global distribution of per-capita gross domestic product shows a striking correlation between malaria and poverty, and malaria-endemic countries also have lower rates of economic growth. There are multiple channels by which malaria impedes development, including effects on fertility, population growth, saving and investment, worker productivity, absenteeism, premature mortality and medical costs.
Plasmodium falciparum chloroquine resistance is a major cause of worldwide increases in malaria mortality and morbidity. Recent laboratory and
clinical studies have associated chloroquine resistance with point mutations in the gene pfcrt. However, direct proof of a causal relationship has remained elusive and most models have posited a multigenic basis of resistance.
Here, we provide conclusive evidence that mutant haplotypes of the pfcrt gene product of Asian, African, or South American origin confer chloroquine resistance with characteristic verapamil reversibility
and reduced chloroquine accumulation. pfcrt mutations increased susceptibility to artemisinin and quinine and minimally affected amodiaquine activity; hence, these antimalarials
warrant further investigation as agents to control chloroquine-resistantfalciparum malaria.
Radioisotopic assays involve expense, multistep protocols, equipment, and radioactivity safety requirements which are problematic
in high-throughput drug testing. This study reports an alternative, simple, robust, inexpensive, one-step fluorescence assay
for use in antimalarial drug screening. Parasite growth is determined by using SYBR Green I, a dye with marked fluorescence
enhancement upon contact with Plasmodium DNA. A side-by-side comparison of this fluorescence assay and a standard radioisotopic method was performed by testing known
antimalarial agents against Plasmodium falciparum strain D6. Both assay methods were used to determine the effective concentration of drug that resulted in a 50% reduction
in the observed counts (EC50) after 48 h of parasite growth in the presence of each drug. The EC50s of chloroquine, quinine, mefloquine, artemisinin, and 3,6-bis-ε-(N,N-diethylamino)-amyloxyxanthone were similar or identical by both techniques. The results obtained with this new fluorescence
assay suggest that it may be an ideal method for high-throughput antimalarial drug screening.
The development of drug resistance to affordable drugs has contributed to a global increase in the number of deaths from malaria. This unacceptable situation has stimulated research for new drugs active against multidrug-resistant Plasmodium falciparum parasites. In this regard, we show here that deshydroxy-1-imino derivatives of acridine (i.e., dihydroacridinediones) are selective antimalarial drugs acting as potent (nanomolar K(i)) inhibitors of parasite mitochondrial bc(1) complex. Inhibition of the bc(1) complex led to a collapse of the mitochondrial membrane potential, resulting in cell death (IC(50) approximately 15 nM). The selectivity of one of the dihydroacridinediones against the parasite enzyme was some 5000-fold higher than for the human bc(1) complex, significantly higher ( approximately 200 fold) than that observed with atovaquone, a licensed bc(1)-specific antimalarial drug. Experiments performed with yeast manifesting mutations in the bc(1) complex reveal that binding is directed to the quinol oxidation site (Q(o)) of the bc(1) complex. This is supported by favorable binding energies for in silico docking of dihydroacridinediones to P. falciparum bc(1) Q(o). Dihydroacridinediones represent an entirely new class of bc(1) inhibitors and the potential of these compounds as novel antimalarial drugs is discussed.
Plasmodium falciparum can now be maintained in continuous culture in human erythrocytes incubated at 38°C in RPMI 1640 medium with human serum under an atmosphere with 7 percent carbon dioxide and low oxygen (1 or 5 percent). The original parasite material, derived from an infected Aotus trivirgatus monkey, was diluted more than 100 million times by the addition of human erythrocytes at 3- or 4-day intervals. The parasites continued to reproduce in their normal asexual cycle of approximately 48 hours but were no longer highly synchronous. They have remained infective to Aotus.
Of the thousands of novel compounds that a drug discovery project team invents and that bind to the therapeutic target, only a fraction have sufficient ADME (absorption, distribution, metabolism, elimination) properties, and acceptable toxicology properties, to become a drug product that will successfully complete human Phase I clinical trials. Drug-Like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization, Second Edition, provides scientists and students the background and tools to understand, discover, and develop optimal clinical candidates. This valuable resource explores physiochemical properties, including solubility and permeability, before exploring how compounds are absorbed, distributed, and metabolized safely and stably. Review chapters provide context and underscore the importance of key concepts such as pharmacokinetics, toxicity, the blood-brain barrier, diagnosing drug limitations, prodrugs, and formulation. Building on those foundations, this thoroughly updated revision covers a wide variety of current methods for the screening (high throughput), diagnosis (medium throughput) and in-depth (low throughput) analysis of drug properties for process and product improvement. From conducting key assays for interpretation and structural analysis, the reader learns to implement modification methods and improve each ADME property. Through valuable case studies, structure-property relationship descriptions, and structure modification strategies, Drug-Like Properties, Second Edition, offers tools and methods for ADME/Tox scientists through all aspects of drug research, discovery, design, development, and optimization. Provides a comprehensive and valuable working handbook for scientists and students in medicinal chemistry Includes expanded coverage of pharmacokinetics fundamentals and effects Contains updates throughout, including the authors' recent work in the importance of solubility in drug development; new and currently used property methods, with a reduction of seldom-used methods; and exploration of computational modeling methods.
A series of [(o-acylaryl)oxy]propanolamines have been prepared and evaluated for multidrug resistance-reverting activity in a human tumor cell model. Structure-activity relationship studies indicate that the phenylpropiophenone moiety as well as the substitution pattern at the nitrogen atom is crucial for activity of the compounds. Incorporation of the ether oxygen into a benzofuran substructure, which renders the compound an arylethanolamine, decreased biologic activity. Highest activity could be observed with the arylpiparazines 4f-h, which not only completely restored daunomycin sensitivity but also showed moderate activity in restoring etoposide toxicity.
Prototropic tautomerism in 4-quinolone-3-carboxylic acid derivatives has been studied with particular emphasis on the influence of the ring substituents on the equilibrium. The techniques used include UV, 1H-NMR, 13C-NMR (solution and 13C-NMR CP/MAS (solid state) and semiempirical and ab initio calculations. The pKa values of some quinolone derivatives have been determined and correlated with data obtained from semiempirical methods.
1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylic acid (1), a previously reported potent inhibitor of bacterial DNA gyrase, was found to be interactive with mammalian topoisomerase II (topo II). In a DNA-cleavage assay using topo II isolated from HeLa cells, 1 exhibited an EC50 value of 7.6 muM (VP-16; EC50 = 0.81 muM). A series of analogues modified at the 1-, 2-, 3-, 5-, and 7-positions of 1 were subsequently made and assessed for topo II inhibition. Compound 1 was considerably more potent than derivatives where the 1-substituent was alkyl, aryl, or H, or when N-c-C3H5 was replaced with S. The descarboxyl (i.e., 3-H) analogue had potency comparable to that of 1; when both these compounds were substituted at the 2-position with methyl or phenyl, an interesting relationship between activity and the conformation of the carboxyl group emerged. Upon replacement of the 5-H of 1 with NH2 or F, sustained potency was seen. No enhancement of activity was evident upon replacing the 7-substituent of 1 with other pyridinyl groups, 4-methyl-1-piperazinyl, or pyrrolidinyl groups; however, the 7-(4-hydroxyphenyl) analogue (CP-115,953) was 6-fold more potent than 1. The topo II inhibitory properties of 1 translated to modest in vitro cytotoxicity and in vivo activity versus P388.
Novel quinolinonyl diketo acids were designed to obtain integrase (IN) inhibitors selectively active against the strand transfer (ST) step of the HIV integration process. Those new compounds are characterized by a single aryl diketo acid (DKA) chain in comparison to 4, a bifunctional diketo acid reported by our group as an anti-IN agent highly potent against both the 3'-processing and ST steps. Compound 6d was the most potent derivative in IN enzyme assays, while 6i showed the highest potency against HIV-1 in acutely infected cells. The selective inhibition of ST suggested the newly designed monofunctional DKAs bind the IN-DNA acceptor site without affecting the DNA donor site.
One dozen of tailormade model 3-fluoro-2(1H)-quinolinones were synthesized, in order to be investigated by UV-, IR- and NMR spectroscopic techniques. All of these compounds were found to exist predominantly, if not exclusively, in the lactam (carboxamide, 1,2-dihydro-2-oxoquinoline) form. No tautomeric lactim (iminol, azaphenol) structure was detected. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008).
The derivatization of the fluoroquinolone ciprofloxacin greatly increases its antimalarial activity by combining bioorganometallic chemistry and the prodrug approach. Two new achiral compounds 2 and 4 were found to be 10- to 100-fold more active than ciprofloxacin against Plasmodium falciparum chloroquine-susceptible and chloroquine-resistant strains. These achiral derivatives killed parasites more rapidly than did ciprofloxacin. Compounds 2 and 4 were revealed to be promising leads, creating a new family of antimalarial agents.
Plasmodium falciparum can now be maintained in continuous culture in human erythrocytes incubated at 38 degrees C in RPMI 1640 medium with human serum under an atmosphere with 7 percent carbon dioxide and low oxygen (1 or 5 percent). The original parasite material, derived from an infected Aotus trivirgatus monkey, was diluted more than 100 million times by the addition of human erythrocytes at 3- or 4-day intervals. The parasites continued to reproduce in their normal asexual cycle of approximately 48 hours but were no longer highly synchronous. The have remained infective to Aotus.
A number of quinolones and related antibacterial compounds were screened for activity against calf thymus topoisomerase II
by using the P4 unknotting and DNA breakage assays. Several compounds from different structural classes which inhibited DNA
unknotting with 50% inhibitory concentrations ranging from 8 to 25 micrograms/ml were identified. Two experimental isothiazoloquinolones
from this group, designated A-65281 and A-65282, were also found to induce considerable DNA breakage mediated by calf thymus
topoisomerase II, with 32P-end-labeled pBR322 as the substrate. These compounds were nearly as potent as teniposide, with
DNA breakage activity evident at concentrations as low as 4 micrograms/ml. However, some differences in DNA cleavage patterns
from those with teniposide were evident. These studies have thus identified a new class of agents which have activity against
both bacterial and eukaryotic type II topoisomerases. The implications of these data for the selectivity of topoisomerase-directed
compounds and the potential toxicity of such compounds developed as antibacterial agents are discussed.
To improve upon the activity and properties of the 3-aryl-7-chloro-3,4- dihydro-1,9(2H,10H)-acridinediones, a variety of 1-[(alkylamino)alkylene]imino derivatives (3) were prepared and shown to be highly active antimalarial agents in both rodents and primates. Among structural modifications prepared, including N10-alkyl and C2-substituted analogs, removal of the C9 oxygen, and introduction of an imino side chain at C9, the imines of the N10-H acridinediones were the most active compounds obtained. The [3-(N,N- dimethylamino)propyl]imino derivative of 7-chloro-3-(2,4-dichlorophenyl)-3,4-dihydro-1,9(2H,10H)- acridinedione (9aa) proved to be highly active in advanced studies in primates.
Two compounds of the quinoline ester series, WR 197236 (6-butyl-4-hydroxy-3-methoxycarbonyl-7-β-phenoxyethoxyquinoline) and
WR 194905 (4-acetoxy-6-decyloxy-7-isopropoxy-3-methoxycarbonyl-quinoline), exhibit anti-relapse activity against sporozoite-induced
Plasmodium cynomolgi B infections in rhesus monkeys. Both the compounds have been found to be curative when given intramusculary in 7 daily doses
of 15 mg/kg, and no relapses were observed during the observation period of 120 d.
The fluoroquinolone antibiotics are structurally related to nalidixic acid. Their primary antibacterial action appears to be mainly due to inhibition of DNA gyrase (DNA topoisomerase II). We determined the activity of several fluoroquinolones in vitro against two strains of Plasmodium falciparum, FCC1 (chloroquine susceptible) and VNS (chloroquine resistant). [3H]hypoxanthine incorporation by malarial parasites was determined at 48 and 96 h. The molarity at which each agent caused a 50% decrease in the incorporation of [3H]hypoxanthine compared with that of drug-free controls was defined as the 50% inhibitory concentration. The fluoroquinolones evaluated were amifloxacin, ciprofloxacin, enoxacin, norfloxacin, ofloxacin, and pefloxacin. Other DNA gyrase inhibitors tested were nalidixic acid, oxolinic acid, novobiocin, and coumermycin A1. Among the fluoroquinolones, ciprofloxacin had the lowest 50% inhibitory concentrations at 48 h against both chloroquine-susceptible and -resistant strains of P. falciparum, (0.26 +/- 0.08) x 10(-4) and (0.38 +/- 0.15) x 10(-4) M, respectively (mean +/- standard deviation). Enoxacin had the lowest 50% inhibitory concentrations against FCC1 and VNS at 96 h, 0.23 x 10(-5) and (0.06 +/- 0.04) x 10(-5) M, respectively. With the VNS strain, fractional inhibitory concentration indexes for the combination of ciprofloxacin and tetracycline were calculated at 48 and 96 h to be 0.93 and 0.79, respectively, indicating modest additive effects. The combination of novobiocin with ciprofloxacin showed indifference in the same system. The antimalarial effects of some fluoroquinolones occur at achievable serum concentrations. Whether inhibition of DNA gyrase contributes to the antimalarial activity of the fluoroquinolones is unknown at present.
Methyl-4H-4-chinolon (I) kann in Gegenwart von Acetanhydrid und Eisessig mit den Aldehyden (II) zu den Olefinen (III) kondensiert werden.
The genotoxic potency of certain classes of topoisomerase II poisons is correlated with their affinity to the topoisomerase protein rather than with the presence of 'classical' structural alerts for DNA reactivity: bacterial topoisomerase II poisons (specifically named gyrase inhibitors) are highly genotoxic in prokaryotic systems; mammalian topoisomerase II poisons are potent mutagens/clastogens in eukaryotic systems. Studies with bacterial, lower eukaryotic and mammalian genotoxicity tests were performed to draw structure-activity conclusions and address risk-benefit considerations for the class of quinolone gyrase inhibitors. All 17 gyrase inhibitors investigated in this study showed genotoxic activity in Salmonella typhimurium strain TA102 and the SOS test. The genotoxic and the toxic activities increased in a highly parallel fashion from the parent compounds, nalidixic acid and oxolinic acid, to the new generation fluoroquinolones. Generally, the most potent fluoroquinolones also show clear-cut positive effects in eukaryotic test systems, although at concentrations 100-1000-fold higher than those effective in bacteria and also 100-1000-fold higher than the minimal genotoxic concentrations of antitumour topoisomerase II inhibitors (ellipticine, teniposide, mAMSA) used as reference compounds. However, subtle structural modifications of the quinolones can strongly diminish the preferential genotoxicity in the prokaryotic test systems.
A series of [(o-acylaryl)oxy]propanolamines have been prepared and evaluated for multidrug resistance-reverting activity in a human tumor cell model. Structure-activity relationship studies indicate that the phenylpropiophenone moiety as well as the substitution pattern at the nitrogen atom is crucial for activity of the compounds. Incorporation of the ether oxygen into a benzofuran substructure, which renders the compound an arylethanolamine, decreased biologic activity. Highest activity could be observed with the arylpiparazines 4f-h, which not only completely restored daunomycin sensitivity but also showed moderate activity in restoring etoposide toxicity.
1-Cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-ox o-3-quinolinecarboxylic acid (1), a previously reported potent inhibitor of bacterial DNA gyrase, was found to be interactive with mammalian topoisomerase II (topo II). In a DNA-cleavage assay using topo II isolated from HeLa cells, 1 exhibited an EC50 value of 7.6 microM (VP-16; EC50 = 0.81 microM). A series of analogues modified at the 1-, 2-, 3-, 5-, and 7-positions of 1 were subsequently made and assessed for topo II inhibition. Compound 1 was considerably more potent than derivatives where the 1-substituent was alkyl, aryl, or H, or when N-c-C3H5 was replaced with S. The descarboxyl (i.e., 3-H) analogue had potency comparable to that of 1; when both these compounds were substituted at the 2-position with methyl or phenyl, an interesting relationship between activity and the conformation of the carboxyl group emerged. Upon replacement of the 5-H of 1 with NH2 or F, sustained potency was seen. No enhancement of activity was evident upon replacing the 7-substituent of 1 with other pyridinyl groups, 4-methyl-1-piperazinyl, or pyrrolidinyl groups; however, the 7-(4-hydroxyphenyl) analogue (CP-115,953) was 6-fold more potent than 1. The topo II inhibitory properties of 1 translated to modest in vitro cytotoxicity and in vivo activity versus P388.
The development of chloroquine as an antimalarial drug and the subsequent evolution of drug-resistant Plasmodium strains had major impacts on global public health in the 20th century. In P. falciparum the cause of the most lethal human malaria, chloroquine resistance is linked to multiple mutations in PfCRT, a protein that
likely functions as a transporter in the parasite’s digestive vacuole membrane. Rapid diagnostic assays for PfCRT mutations
are already employed as surveillance tools for drug resistance. Here, we review recent field studies that support the central
role of PfCRT mutations in chloroquine resistance. These studies suggest chloroquine resistance arose in ⩾4 distinct geographic
foci and substantiate an important role of immunity in the outcomes of resistant infections after chloroquine treatment. P. vivax which also causes human malaria, appears to differ from P. falciparum in its mechanism of chloroquine resistance. Investigation of the resistance mechanisms and of the role of immunity in therapeutic
outcomes will support new approaches to drugs that can take the place of chloroquine or augment its efficiency
Continued and sustainable improvements in antimalarial medicines through focused research and development are essential for the world's future ability to treat and control malaria. Unfortunately, malaria is a disease of poverty, and despite a wealth of scientific knowledge there is insufficient market incentive to generate the competitive, business-driven industrial antimalarial drug research and development that is normally needed to deliver new products. Mechanisms of partnering with industry have been established to overcome this obstacle and to open up and build on scientific opportunities for improved chemotherapy in the future.
Approximately 40% of the world population live in areas with the risk of malaria. Each year, 300-500 million people suffer from acute malaria, and 0.5-2.5 million die from the disease. Although malaria has been widely eradicated in many parts of the world, the global number of cases continues to rise. The most important reason for this alarming situation is the rapid spread of malaria parasites that are resistant to antimalarial drugs, especially chloroquine, which is by far the most frequently used. The development of new antimalarial drugs has been neglected since the 1970s owing to the end colonialism, changes in the areas of military engagement, and the restricted market potential. Only in recent years, in part supported by public funding programs, has interest in the development of antimalarial drugs been renewed. New data available from the recently sequenced genome of the malaria parasite Plasmodium falciparum and the application of methods of modern drug design promise to bring significant development in the fight against this disease.
Due to growing problems with drug resistance, there is an outstanding need for new, cost-effective drugs for the treatment of malaria. The 4-aminoquinolines have provided a number of useful antimalarials, and Plasmodium falciparum, the causative organism for the most deadly form of human malaria, is generally slow to develop resistance to these drugs. Therefore, diverse screening libraries of quinolines continue to be useful for antimalarial drug discovery. We report herein the development of an efficient method for producing libraries of 4-aminoquinolines variant in the side chain portion of the molecule. The effects of these substitutions were evaluated by screening this library for activity against P. falciparum, revealing four potent compounds active against drug-resistant strains.
For Abstract see ChemInform Abstract in Full Text.
In the past 21 years, a modest increase in the range of antimalarial drugs approved for clinical use has been complemented by a more impressive expansion in the analysis and understanding of the molecular mechanisms underlying resistance to these agents. Such resistance is a major factor in the increasing difficulty in controlling malaria, and important developments during this period are recounted here.
Several 1-[(2-hydroxy-ethoxy)methyl]-3-carbethoxy-4(1H)quinolones (2a-l) and l-[(2-hydroxy-ethoxy)methyl]-4(1H)quinolone-3-carboxylic acids (3a-j and 3l) were synthesized and 2a-j, 2l and 3a-j, 3l were evaluated against herpes simplex virus type 1 (HSV-1), employing a one-pot reaction: silylation of the desired quinolone (BSTFA 1% TMCS) followed by equimolar amount addition of 1,3-dioxolane, chlorotrimethylsilane and KI, at room temperature. The acyclonucleosides 2a-l were obtained in 40-77% yields. The esters 2a-j and 2l were subsequently converted into the corresponding hydroxyacids 3 in 40-70% yields. Attempts of hydrolysis of 2k produced only a mixture of degradation products. Antiviral activity of 2 and 3 on HSV-1 virus infection was assessed by the virus yield assay. Except for compounds 2i and 3e, the acyclonucleosides were found to reduce the virus yield by 70-99% at the concentration of 50 microM, being the acids, in general, more effective inhibitors than their corresponding esters. Compounds 3j and 2d exhibited antiviral activity against HSV-1 virus with EC50 of 0.7+/-0.04 and 0.8+/-0.09 microM, respectively. Both compounds were not toxic towards the Vero cell line.
Since ancient times, humankind has had to struggle against the persistent onslaught of pathogenic microorganisms. Nowadays, malaria is still the most important infectious disease worldwide. Considerable success in gaining control over malaria was achieved in the 1950s and 60s through landscaping measures, vector control with the insecticide DDT, and the widespread administration of chloroquine, the most important antimalarial agent ever. In the late 1960s, the final victory over malaria was believed to be within reach. However, the parasites could not be eradicated because they developed resistance against the most widely used and affordable drugs of that time. Today, cases of malaria infections are on the rise and have reached record numbers. This review gives a short description of the malaria disease, briefly addresses the history of antimalarial drug development, and focuses on drugs currently available for malaria therapy. The present knowledge regarding their mode of action and the mechanisms of resistance are explained, as are the attempts made by numerous research groups to overcome the resistance problem within classes of existing drugs and in some novel classes. Finally, this review covers all classes of antimalarials for which at least one drug candidate is in clinical development. Antimalarial agents that are solely in early development stages will be addressed in a separate review.
In the present article we examine the antiplasmodial activities of novel quinolone derivatives bearing extended alkyl or alkoxy side chains terminated by a trifluoromethyl group. In the series under investigation, the IC50 values ranged from 1.2 to approximately 30 nM against chloroquine-sensitive and multidrug-resistant Plasmodium falciparum strains. Modest to significant cross-resistance was noted in evaluation of these haloalkyl- and haloalkoxyquinolones for activity against the atovaquone-resistant clinical isolate Tm90-C2B, indicating that a primary target for some of these compounds is the parasite cytochrome bc1 complex. Additional evidence to support this biochemical mechanism includes the use of oxygen biosensor plate technology to show that the quinolone derivatives block oxygen consumption by parasitized red blood cells in a fashion similar to atovaquone in side-by-side experiments. Atovaquone is extremely potent and is the only drug in clinical use that targets the Plasmodium bc1 complex, but rapid emergence of resistance to it in both mono- and combination therapy is evident and therefore additional drugs are needed to target the cytochrome bc1 complex which are active against atovaquone-resistant parasites. Our study of a number of halogenated alkyl and alkoxy 4(1H)-quinolones highlights the potential for development of "endochin-like quinolones" (ELQ), bearing an extended trifluoroalkyl moiety at the 3-position, that exhibit selective antiplasmodial effects in the low nanomolar range and inhibitory activity against chloroquine and atovaquone-resistant parasites. Further studies of halogenated alkyl- and alkoxy-quinolones may lead to the development of safe and effective therapeutics for use in treatment or prevention of malaria and other parasitic diseases.
Human African trypanosomiasis (HAT), a major health concern in sub-Saharan Africa, is caused by the protozoan parasite Trypanosoma brucei. Recent studies have shown that a cathepsin B like protease, TbcatB, is essential to the survival of T. brucei in vitro (Mackey, Z. B.; O'Brien, T. C.; Greenbaum, D. C.; Blank, R. B.; McKerrow, J. H. J. Biol. Chem. 2004, 279, 48426-48433). Herein, we describe the first inhibitors of TbcatB, a series of purine nitriles. The compounds are potent trypanocides, killing the parasite with a high degree of selectivity over a panel of three human cell lines. In addition, a predictive model of trypanocidal activity was developed on the basis of potency against TbcatB and various calculated physical property descriptors.
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manuscript; available in PMC
Bioorg Med Chem. Author manuscript; available in PMC 2011 April 1.