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Evaluation of Diarylureas for Activity Against Plasmodium falciparum
Abstract
A library of diarylurea insulin-like growth factor 1 receptor inhibitors was screened for activity against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum. The 4-aminoquinaldine-derived diarylureas displayed promising antimalarial potency. Further exploration of the B ring of 4-aminoquinaldinyl ureas allowed identification of several quinaldin-4-yl ureas 4{13, 39} and 4{13, 58} sufficiently potent against both 3D7 and K1 strains to qualify as bone fide leads.
... falciparum 3D7) EC 50 = 0.11 µM (P. falciparum K1) [20] PQ401 EC50 = 0.053 µM (P. falciparum 3D7 and K1) [20] 28 EC50 = 0.32 µM (P. ...
... falciparum K1) [20] PQ401 EC50 = 0.053 µM (P. falciparum 3D7 and K1) [20] 28 EC50 = 0.32 µM (P. falciparum 3D7) [20] 29 EC50 = 0.031 µM (P. ...
... falciparum 3D7 and K1) [20] 28 EC50 = 0.32 µM (P. falciparum 3D7) [20] 29 EC50 = 0.031 µM (P. falciparum 3D7) EC50 = 0.11 µM (P. ...
Antimicrobials have allowed medical advancements over several decades. However, the continuous emergence of antimicrobial resistance restricts efficacy in treating infectious diseases. In this context, the drug repositioning of already known biological active compounds to antimicrobials could represent a useful strategy. In 2002 and 2003, the SARS-CoV pandemic immobilized the Far East regions. However, the drug discovery attempts to study the virus have stopped after the crisis declined. Today’s COVID-19 pandemic could probably have been avoided if those efforts against SARS-CoV had continued. Recently, a new coronavirus variant was identified in the UK. Because of this, the search for safe and potent antimicrobials and antivirals is urgent. Apart from antiviral treatment for severe cases of COVID-19, many patients with mild disease without pneumonia or moderate disease with pneumonia have received different classes of antibiotics. Diarylureas are tyrosine kinase inhibitors well known in the art as anticancer agents, which might be useful tools for a reposition as antimicrobials. The first to come onto the market as anticancer was sorafenib, followed by some other active molecules. For this interesting class of organic compounds antimicrobial, antiviral, antithrombotic, antimalarial, and anti-inflammatory properties have been reported in the literature. These numerous properties make these compounds interesting for a new possible pandemic considering that, as well as for other viral infections also for CoVID-19, a multitarget therapeutic strategy could be favorable. This review is meant to be an overview on diarylureas, focusing on their biological activities, not dwelling on the already known antitumor activity. Quite a lot of papers present in the literature underline and highlight the importance of these molecules as versatile scaffolds for the development of new and promising antimicrobials and multitarget agents against new pandemic events.
... Since the disclosure of ART (10) as an excellent antimalarial, Chinese scientists synthesized various novel ART-derived semisynthetic derivatives such as dihydroartemisinin (DHA) (18), artemether (AM) (19), arteether (20), and artesunic acid (21) or its sodium salt (artesunate [AS]) ( Figure 4). Several boundaries are associated with ART (10) such as stability (decomposition and breakage of peroxide linkage), solubility (low solubility in both oil and water), poor oral bioavailability (half-life [t 1/2 ], 1-4 hours), rate of recrudescence of parasitaemia as well as cost (extracted from plant with a maximum yield of 0.1%) not only restricts its utilization as a drug yet; it also confines its therapeutic value and accounts for all the primary initiatives behind the development of various semisynthetic derivatives of ART. ...
... In comparison to 10, these semisynthetic analogues have shown promising antiplasmodial activity against multidrug-resistant malaria strains with improved oil/water solubility and are currently the drugs of choice for the treatment of malaria. [114][115][116] A water-soluble succinate ester derivative of DHA (18), that is, artesunic acid (21) or its sodium salt (AS) was developed for the quick relief in case of the complicated malaria. 117 The scalability of AS (21) via intravenous (IV) route was also examined through various clinical trials. ...
... [118][119][120] To avoid the development of parasite resistance against clinically used endoperoxides, in later year's AS (21) in combination with mefloquine (5) frequently utilized under ACT. [121][122][123][124] F I G U R E 3 Mechanism of action of artemisinin-derived drugs F I G U R E 4 First-generation of artemisinin-derived drugs (18)(19)(20)(21)(22) TIWARI AND CHAUDHARY | 7 ...
According to WHO World Malaria Report (2018), nearly 219 million new cases of malaria occurred and a total no. of 435 000 people died in 2017 due to this infectious disease. This is due to the rapid spread of parasite‐resistant strains. Artemisinin (ART), a sesquiterpene lactone endoperoxide isolated from traditional Chinese herb Artemisia annua, has been recognized as a novel class of antimalarial drugs. The 2015 “Nobel Prize in Physiology or Medicine” was given to Prof Dr Tu Youyou for the discovery of ART. Hence, ART is termed as “Nobel medicine.” The present review article accommodates insights from the chronological advancements and direct statistics witnessed during the past 48 years (1971‐2019) in the medicinal chemistry of ART‐derived antimalarial endoperoxides, and their clinical utility in malaria chemotherapy and drug discovery.
... In an initial pharmacokinetic investigation of MMV665852, this symmetrical N,N 0 -diaryl urea was character-ized by a half-life of 4.7 h and C max of 4.4 lM at a 46.3 mg/kg oral dose. 9 Thus, this very simple compound offers intriguing possibilities for further optimization, although this is tempered by its high Log P of 5.2, and the low aqueous solubility 14 and potential pharmacological promiscuity 12,13,15,16 of this compound class. Following the discovery of MMV665852, two subsequent studies 17,18 established an initial SAR for this compound series: 1) substitution at positions 3 and 4 of the phenyl rings with H, F, Cl, CN, and CF 3 groups was optimal; 2) substitution at positions 3 and 4 of the phenyl rings with OCH 3 , NH 2 3) replacement of one of the phenyl rings with alkyl substituents diminished or abolished activity; 4) cyclization of the urea to imidazoline-2-ones abolished activity; and 5) replacement of the urea with carbamates, thioureas, sulfonamides, or oxalamides diminished or abolished activity. ...
... Substitution of one of the 4-fluoro-3-trifluromethylphenyl substructures of 1 with azaheterocycles 6-10 decreased lipophilicity, and with the exception of 8 and 9, increased solubility significantly. Replacing one of the 4-fluoro-3-trifluromethylphenyl substructures of 1 with benzoic acids (11,12), benzamides (13,14), a benzonitrile (15) or an acetophenone (16) Twelve of twenty N,N-diaryl ureas (Table 1) had low intrinsic clearance values in human and mouse liver microsomes and three Table 1 Physicochemical and in vitro ADME properties for N,N 0 -diaryl ureas 1-20. ...
... Ar of these (1,5,17) were the most lipophilic of the series, possibly reflecting high protein binding in the microsomal test system. The eight N,N-diaryl ureas with intermediate to high intrinsic clearance contained either pyridine nitrogen atoms (4, 6-10) or primary carboxamide functional groups (13,14). Notably, N,N-diaryl ureas with 3-trifluoromethyl-4-pyridyl substructures (2,(18)(19)(20) were metabolically stable. ...
N,N'-Diaryl ureas have recently emerged as a new antischistosomal chemotype. We now describe physicochemical profiling, in vitro ADME, plasma exposure, and ex vivo and in vivo activities against Schistosoma mansoni for twenty new N,N'-diaryl ureas designed primarily to increase aqueous solubility, but also to maximize structural diversity. Replacement of one of the 4-fluoro-3-trifluoromethylphenyl substructures of lead N,N'-diaryl urea 1 with azaheterocycles and benzoic acids, benzamides, or benzonitriles decreased lipophilicity, and in most cases, increased aqueous solubility. There was no clear relationship between lipophilicity and metabolic stability, although all compounds with 3-trifluoromethyl-4-pyridyl substructures were metabolically stable. N,N'-diaryl ureas containing 4-fluoro-3-trifluoromethylphenyl, 3-trifluoromethyl-4-pyridyl, 2,2-difluorobenzodioxole, or 4-benzonitrile substructures had high activity against ex vivo S. mansoni and relatively low cytotoxicity. N,N-diaryl ureas with 3-trifluoromethyl-4-pyridyl and 2,2-difluorobenzodioxole substructures had the highest exposures whereas those with 4-fluoro-3-trifluoromethylphenyl substructures had the best in vivo antischistosomal activities. There was no direct correlation between compound exposure and in vivo activity.
... In recent years, there has been an increasing interest in 1,3-diphenylureas which are also known as N,N ıdiphenylureas due to their wide range of chemical and biological applications [1,2]. It is known that these compounds show good pharmacological activities including anticancer [3][4][5], antimalarial [6,7], anti-Alzheimer [8], antiviral [9], carbonic anhydrase I and II inhibitors [2], anti-tuberculosis [10] and antidepressant [11,12]. Regorafenib named 4-(4-(((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl}amino)-3-fluoro phenoxy)-N-methylpyridine-2-carboxamide which is a diphenylurea derivative drug shows the pharmaceutical properties as multikinase inhibitor of VEGFR-2, -3, c-Kit, p38 MAP kinase etc. and uses at the treatment of colorectal, hepatocellular and gastrointestinal stromal cancers [3]. ...
... The synthesis of unsymmetrical diphenylurea derivatives is an important issue due to their superior biological applications and chemical treatments including usage as intermediate, linker in complex synthesis and also protection of amino groups. Synthesis of target structures can be carried out with aniline derivatives and phosgene [14,15], triphosgene (BTC, bis(trichloromethyl) carbonate) [16], 1,1'carbonyldiimidazole (CDI) [7], S,S-dimethyl dithiocarbonate [17], 1,1-carbonylbis benzotriazole [18] or carbon monoxide/dioxide with catalysts [19,20] as CO sources. In addition, alternative synthesis method is Curtius rearrangement which begins with a different starti starting material, substituted benzoyl chlorides. ...
A new organic compound, 1-(3,5-difluorophenyl)-3-(2-nitrophenyl)urea was synthesized from 2-nitroaniline, 3,5-difluoroaniline and triphosgene in sequential two steps with 92% yield. The product was crystallized by the slow evaporation using THF and ethyl acetate solvent system to obtain its single crystal. The pure crystals were characterized with melting point, FT-IR, 1H NMR, 13C NMR and MS. The structure of the compound was brought to light by X-ray single-crystal structure determination. Density functional theory calculations were applied by using (DFT/B3LYP) method with the 6-311G(d,p) basis set level. The potential energy surface (PES) scanning was performed to determine the stability of the molecule. Frontier molecular orbitals of the compound were calculated. AIM charge and MEP analyzes were performed.
... Humankind is prone to infection from five different forms of single-celled eukaryotic Plasmodium parasites (primarily Plasmodium falciparum and Plasmodium vivax). [6][7][8][9][10][11][12] Feminine Anopheles sp. mosquitoes distribute these parasites, and humans are the only mammal hosts of these parasites. ...
The demand for novel, fast-acting, and effective antimalarial medications is increasing exponentially. Multidrug resistant forms of malarial parasites, which are rapidly spreading, pose a serious threat to global health. Drug resistance has been addressed using a variety of strategies, such as targeted therapies, the hybrid drug idea, the development of advanced analogues of pre-existing drugs, and the hybrid model of resistant strains control mechanisms. Additionally, the demand for discovering new potent drugs grows due to the prolonged life cycle of conventional therapy brought on by the emergence of resistant strains and ongoing changes in existing therapies. The 1,2,4-trioxane ring system in artemisinin (ART) is the most significant endoperoxide structural scaffold and is thought to be the key pharmacophoric moiety required for the pharmacodynamic potential of endoperoxide-based antimalarials. Several derivatives of artemisinin have also been found as potential treatments for multidrug-resistant strain in this area. Many 1,2,4-trioxanes, 1,2,4-trioxolanes, and 1,2,4,5-tetraoxanes derivatives have been synthesised as a result, and many of these have shown promise antimalarial activity both in vivo and in vitro against Plasmodium parasites. As a consequence, efforts to develop a functionally straight-forward, less expensive, and vastly more effective synthetic pathway to trioxanes continue. This study aims to give a thorough examination of the biological properties and mode of action of endoperoxide compounds derived from 1,2,4-trioxane-based functional scaffolds. The present system of 1,2,4-trioxane, 1,2,4-trioxolane, and 1,2,4,5-tetraoxane compounds and dimers with potentially antimalarial activity will be highlighted in this systematic review (January 1963-December 2022).
... The first two species are responsible for most infections worldwide, Plasmodium falciparum, being the most virulent culprit, has a major contribution in number of deaths associated with malaria. [4][5][6][7][8] Moreover, the widespread resistance of malaria parasites to the affordable antimalarial drugs (chloroquine, pyrimethamine), adds to the plight, thereby challenging the existing disease control measures. Unfortunately, the drugresistant parasites have resulted in millions of deaths over the last few decades. ...
A new series of 1,2,4-trioxanes 9a1-a4, 9b1-b4, 10–13 and 9c1-c4 were synthesized and evaluated against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice via oral and intramuscular (i.m.) routes. Adamantane-based trioxane 9b4, the most active compound of the series, provided 100% protection to the infected mice at the dose 48 mg/kg × 4 days and 100% clearance of parasitemia at the dose 24 mg/kg × 4 days via oral route. Adamantane-based trioxane 9b4, is twice active than artemisinin.
We have also studied the photooxygenation behaviour of allylic alcohols 6a-b (3-(4-alkoxynaphthyl)-but-2-ene-1-ols) and 6c (3-[4-(tert-butyl-dimethyl-silanyloxy)-naphthalen-1-yl]-but-2-en-1-ol). Being behaving as dienes, they furnished corresponding endoperoxides, while behaving as allylic alcohols, they yielded β-hydroxyhydroperoxides. All the endoperoxides (7a-c) and β-hydroxyhydroperoxides (8a-c) have been separately elaborated to the corresponding 1,2,4-trioxanes, except from endoperoxide 7c. It is worthy to note that TBDMS protected naphthoyl endoperoxide 7c unable to deliver 1,2,4-trioxane, which demonstrated the strength of the O-Si bond is not easy to cleave under acidic condition.
... Worth mentioning is that the presence of N,N'-diarylurea compounds in medicinal chemistry is quite remarkable, owing to the versatility of this scaffold, and thus their broad spectrum of biological activities. Particularly, they have been widely studied as anticancer (10)(11)(12), insecticidal (13), and antimicrobial agents (14)(15), as well as in immunology (16)(17) and in other infectious diseases (18)(19). ...
In recent years, N,N'-diarylureas have emerged as a promising chemotype for the treatment of schistosomiasis, a disease that poses a considerable health burden to millions of people worldwide. Here, we report a novel series of N,N'-diarylureas featuring the scarcely explored pentafluorosulfanyl group. Low IC50 values for Schistosoma mansoni newly transformed schistosomula (0.6 - 7.7 μM) and adult worms (0.1 - 1.6 μM) were observed. Four selected compounds, highly active in presence of albumin (>70% at 10 μM), endowed with decent cytotoxicity profile (SI against L6 cells >8.5) and good microsomal hepatic stability (>62.5% of drug remaining after 60 min), were tested in S. mansoni infected mice. Despite the promising in vitro worm killing potency, none of them showed significant activity in vivo. Pharmacokinetic data showed a slow absorption, with maximal drug concentrations reached after 24 h of exposure. Finally, no direct correlation between drug exposure and in vivo activity was found. Thus, further investigations are needed to better understand the underlying mechanisms of SF5-containing N,N'-diarylureas.
... Procedure B [75]: To a DMSO solution of 3f (0.1 mmol in 2 mL DMSO) was added a solution of appropriate freshly prepared isocyanate derivative (0.18 mmol in 2 mL DMSO) at room temperature. The reaction mixture was stirred at room temperature for 2 h followed by reflux at 80°C overnight. ...
A series of diarylurea derivatives comprising 2,4-diarylpyrimidines were synthesized based on a combination of postulated molecular hybridization design and failed-ligands repurposing approaches, which enabled the discovery of novel potential antiproliferative agents. Towards credible biological evaluation, an in vitro anticancer activity assay was conducted employing a library of 60 cancer cell lines constituting nine panels representing blood, lung, colon, CNS, skin, ovary, renal, prostate, and breast cancers. The results revealed high effectiveness and broad-spectrum anticancer activity of compounds 4m and 4g. Five-dose assay of compounds 4m and 4g proved their high potency that surpassed that of four standard kinase inhibitors FDA-approved anticancer drugs against many cancer cells. Towards the identification of their molecular target, screening of kinase inhibitory profile employing a panel of 51 kinases involved in cancer revealed inhibition of several kinases from the platelet-derived growth factor/vascular endothelial growth factor receptor (PVR) kinase family, which might mediate, at least in part, the antiproliferative activity. Molecular docking of 4g into the crystal structure of the Feline McDonough Sarcoma (FMS) kinase predicted that it binds to a pocket formed by the juxtamembrane domain, the catalytic loop, and the αE helix, thus stabilizing the inhibited conformation of the kinase. Flow cytometric study of the cytotoxic effects of compound 4g in A549 cells showed it induces dose- and time-dependent apoptotic events leading to cell death. Collectively, this work presents compound 4g as a potential broad-spectrum anticancer agent against multiple cancer types.
... Diarylureas are known to be important pharmacophores in drug discovery (22). Indeed, diarylurea derivatives have been developed as antimalarial (23), antischistosomal (24), antimicrobial (25,26), and anticancer (22,27) agents. We identified the diarylurea compound PQ401 as a hit in the C. elegans screen (described above) that not only blocks the ability of MRSA to kill C. elegans but also induces rapid MRSA membrane permeabilization. ...
Membrane-damaging antimicrobial agents have great potential to treat multidrug-resistant or multidrug-tolerant bacteria against which conventional antibiotics are not effective. However, their therapeutic applications are often hampered due to their low selectivity to bacterial over mammalian membranes or their potential for cross-resistance to a broad spectrum of cationic membrane-active antimicrobial agents. We discovered that the diarylurea derivative compound PQ401 has antimicrobial potency against multidrug-resistant and multidrug-tolerant Staphylococcus aureus . PQ401 selectively disrupts bacterial membrane lipid bilayers in comparison to mammalian membranes. Unlike cationic membrane-active antimicrobials, the neutral form of PQ401 rather than its cationic form exhibits maximum membrane activity. Overall, our results demonstrate that PQ401 could be a promising lead compound that overcomes the current limitations of membrane selectivity and cross-resistance. Also, this work provides deeper insight into the design and development of new noncharged membrane-targeting therapeutics to combat hard-to-cure bacterial infections.
... In 2011, to stimulate drug discovery beyond malaria, Medicines for Malaria Venture (MMV) created the open-source MMV Malaria Box issuing from three previous screenings of libraries from the St. Jude hospital [11,12], from GlaxoSmithKline [13], and from Novartis [14,15]. Further selections resulted in 200 drug-like and 200 probe-like compounds with IC 50 s against Plasmodium falciparum blood stages below 4 µM and a more than 10 times lower cytotoxicity against HEK-293 cells [16]. ...
(1) Background: Neospora caninum is a major cause of abortion in cattle and represents a veterinary health problem of great economic significance. In order to identify novel chemotherapeutic agents for the treatment of neosporosis, the Medicines for Malaria Venture (MMV) Malaria Box, a unique collection of anti-malarial compounds, were screened against N. caninum tachyzoites, and the most efficient compounds were characterized in more detail. (2) Methods: A N. caninum beta-galactosidase reporter strain grown in human foreskin fibroblasts was treated with 390 compounds from the MMV Malaria Box. The IC50s of nine compounds were determined, all of which had been previously been shown to be active against another apicomplexan parasite, Theileria annulata. The effects of three of these compounds on the ultrastructure of N. caninum tachyzoites were further investigated by transmission electron microscopy at different timepoints after initiation of drug treatment. (3) Results: Five MMV Malaria Box compounds exhibited promising IC50s below 0.2 µM. The compound with the lowest IC50, namely 25 nM, was MMV665941. This compound and two others, MMV665807 and MMV009085, specifically induced distinct alterations in the tachyzoites. More specifically, aberrant structural changes were first observed in the parasite mitochondrion, and subsequently progressed to other cytoplasmic compartments of the tachyzoites. The pharmacokinetic (PK) data obtained in mice suggest that treatment with MMV665941 could be potentially useful for further in vivo studies. (4) Conclusions: We have identified five novel compounds with promising activities against N. caninum, the effects of three of these compounds were studies by transmission electron microscopy (TEM). Their modes of action are unknown and require further investigation.
... To avoid hazardous phosgene-containing coupling methods, a strategy using an activated alcohol based on para-nitrophenyl carbonate [13] or an imidazoyl carbamate [18] was employed, however, without formation of the desired product. Likewise, the transformation of the amine functionality of crizotinib into an isocyanate [19,20] and subsequent addition of 1 did not result in the desired carbamate. Therefore, a catalytic carbonylation method from Wang et al. using carbon monoxide, Pd(OAc) 2 , Cu(OAc) 2 and KI was applied [21]. ...
Despite the huge success of tyrosine kinase inhibitors as anticancer agents, severe side effects are a major problem. In order to overcome this drawback, the first hypoxia-activatable 2-nitroimidazole-based prodrugs of the clinically approved ALK and c-MET inhibitor crizotinib were developed. The 2-aminopyridine functionality of crizotinib (essential for target kinase binding) was considered as ideal position for prodrug derivatization. Consequently, two different prodrugs were synthesized with the nitroimidazole unit attached to crizotinib either via carbamoylation (A) or alkylation (B) of the 2-aminopyridine moiety. The successful prodrug design could be proven by docking studies and a dramatically reduced ALK and c-MET kinase-inhibitory potential. Furthermore, the prodrugs showed high stability in serum and release of crizotinib in an enzymatic nitroreductase-based cleavage assay. The in vitro activity of both prodrugs was investigated against ALK- and c-MET-dependent or –overexpressing cells, revealing a distinct hypoxia-dependent activation for prodrug A. Finally, inhibition of c-MET phosphorylation and cell proliferation could also be proven in vivo. In summary of the theoretical, chemical and biological studies, prodrug derivatization of the 2-aminopyridine position can be considered as a promising strategy to reduce the side effects and improve the anticancer activity of crizotinib.
... Malaria is caused by six species of genus Plasmodium viz. P. falciparum, P. vivax, P. malariae, P. ovale curtisi, P. ovale wallikeri and P. knowlesi; out of which P. falciparum and P. vivax are the most fatal for the human beings [8][9][10][11][12][13][14][15][16][17][18][19][20][21]. In addition to this, in the case of P. vivax and P. ovale, parasite exists in a dormant liver stage called hypnozoites, which can stay in liver from few months to a year and thus, responsible for the recrudescence of malaria [22][23][24][25][26][27]. ...
According to WHO “World health statistics 2018”, malaria, alongside acute respiratory infections and diarrhoea, is one of the major infectious disease causing children’s death in between the age of 1-5 years. Similarly, according to another report (2016), malaria accounts for approximately 3.14% of the total disease burden by cause of the world. Although malaria has been widely eradicated in many parts of the world, the global number of cases continues to rise due to rapid spread of malaria parasites that are resistant to antimalarial drugs. Artemisinin 8, a major breakthrough in the antimalarial chemotherapy, was isolated from the plant Artemisia annua in 1972. Its semi-synthetic derivatives such as artemether 9, arteether 10, and artesunic acid 11 are quite effective against multi-drug resistant malaria strains and are currently the drug of choice for the treatment of malaria. In spite of exhibiting excellent antimalarial activity by artemisinin and its derivatives; parallel programmes for the discovery of novel natural and synthetic peroxides were also the area of investigation by medicinal chemists all over the world. In this efforts, after extensive research, natural ozonide (1,2,4-trioxolane) was isolated from Adiantum monochlamys (Pteridaceae) and Oleandra wallichii (Davalliaceae) in 1976. These naturally occurring stable ozonides inspired chemists to investigate this novel class for antimalarial chemotherapy. Thus, in 1992, first identification of unusually stable synthetic antimalarial 1,2,4-trioxolanes was reported. Thus, an unusual entry to the antimalarial chemotherapy of ozonides occurred in early nineties. This review highlights the recent advancements and historical developments observed during the past 42 years (1976-2018) focusing mainly on important ventures of the antimalarial 1,2,4-trioxolanes (ozonides).
... [89,727] MMV006901 (597)iscurrently unreported for antimalarial activity;h owever,K iplin and co-workersi dentified as eries of diaryl ureas (e.g., 598)a sapromisingn ew class of antimalarials. [728] MMV688283 (33), [82] discussed above, featured in the kinetoplastid category of the Pathogen Box, but was reported as an antimalarial, albeit with similarc ompoundsb eing reported as kinetoplastid inhibitors. [729] The same study identified the related MMV687246 (599)a sapromisinga ntiplasmodial. ...
The Pathogen Box is a 400‐strong collection of drug‐like compounds, selected for their potential against several of the world's most important neglected tropical diseases, including trypanosomiasis, leishmaniasis, cryptosporidiosis, toxoplasmosis, filariasis, schistosomiasis, dengue virus and trichuriasis, in addition to malaria and tuberculosis. This library represents an ensemble of numerous successful drug discovery programmes from around the globe, aimed at providing a powerful resource to stimulate open source drug discovery for diseases threatening the most vulnerable communities in the world. This review seeks to provide an in‐depth analysis of the literature pertaining to the compounds in the Pathogen Box, including structure–activity relationship highlights, mechanisms of action, related compounds with reported activity against different diseases, and, where appropriate, discussion on the known and putative targets of compounds, thereby providing context and increasing the accessibility of the Pathogen Box to the drug discovery community.
... The presence of N,N -diarylureas in medicinal chemistry is of great importance due to their broad spectrum of biological activities. They have been widely studied in the field of insecticides [1] and infectious diseases such as malaria [2], schistosomiasis and tuberculosis [3,4], immunology [5,6] and oncology [7], among others. Triclocarban (TCC) is a N,N -diarylurea commonly used as an antimicrobial agent in personal care products such as bar soaps, deodorants, detergents, and other disinfectants [8]. ...
Concerns have been raised about the long-term accumulating effects of triclocarban, a polychlorinated diarylurea widely used as an antibacterial soap additive, in the environment and in human beings. Indeed, the Food and Drug Administration has recently banned it from personal care products. Herein, we report the synthesis, antibacterial activity and cytotoxicity of novel N,N′-diarylureas as triclocarban analogs, designed by reducing one or more chlorine atoms of the former and/or replacing them by the novel pentafluorosulfanyl group, a new bioisostere of the trifluoromethyl group, with growing importance in drug discovery. Interestingly, some of these pentafluorosulfanyl-bearing ureas exhibited high potency, broad spectrum of antimicrobial activity against Gram-positive bacterial pathogens, and high selectivity index, while displaying a lower spontaneous mutation frequency than triclocarban. Some lines of evidence suggest a bactericidal mode of action for this family of compounds.
... As shown in Scheme S1, DOTA-bis(tert-butyl)ester 5 was obtained with a favorable yield (73%) from cyclen according to a previous report [54]. The intermediate 4-isocyanatobenzenesulfonamide for the ureidosulfonamide backbone was prepared by treating 4-aminobenzenesulfonamide with 1,1'-carbonyldiimidazole, and then the product was directly used for the coupling reaction with 1,4-phenylenediamine to form 6 at a 23% yield [55]. After the amide coupling of 5 with ureidosulfonamide 6 in the presence of 1-hydroxybenzotriazole (HOBT) hydrate, 1-ethyl-3-(dimethylaminopropyl)carbodiimide (EDC) hydrochloride, and triethylamine in dimethylformamide, hydrolysis of the product with trifluoroacetic acid (TFA) gave 7 and 8 at 21 and 17% yields, respectively. ...
Hypoxic cells dynamically translocate during tumor growth and after radiotherapy. The most desirable direction for therapy targeting hypoxic cells is combining imaging and therapy (theranostics), which may help realize personalized medicine. Here, we conducted cancer radiotheranostics targeting carbonic anhydrase-IX (CA-IX), which is overexpressed in many kinds of hypoxic cancer cells, using low-molecular-weight ¹¹¹In and ⁹⁰Y complexes with a bivalent ureidosulfonamide scaffold as the CA-IX-binding moiety ([¹¹¹In/⁹⁰Y]US2).
Methods: The targeting ability of [¹¹¹In]US2 was evaluated by in vivo biodistribution study in CA-IX high-expressing (HT-29) tumor-bearing mice. In vivo imaging of HT-29 tumors was carried out using single photon emission computed tomography (SPECT). [⁹⁰Y]US2 was administered to HT-29 tumor-bearing mice to evaluate cancer therapeutic effects.
Results: [¹¹¹In]US2 highly and selectively accumulated within HT-29 tumors (4.57% injected dose/g tumor at 1 h postinjection), was rapidly cleared from the blood pool and muscle after 4 h based on a biodistribution study, and visualized HT-29 tumor xenografts in mice at 4 h postinjection with SPECT. Radionuclide-based therapy with [⁹⁰Y]US2 significantly delayed HT-29 tumor growth compared with that of untreated mice (P = 0.02 on day 28, Student's t-test), without any critical hematological toxicity due to its rapid pharmacokinetics.
Conclusion: These results indicate that cancer radiotheranostics with [¹¹¹In/⁹⁰Y]US2 provides a novel strategy of theranostics for cancer hypoxia.
... It is relevant that some 1,3-diarylureas have been tested with some success against flatworm parasites such as Schistosoma japonicum 50 and Schistosoma mansoni 51 , although no targets were identified in those cases. Also, a family of 1,3-diarylureas with a 4-aminoquinaldinyl as one of the aryl rings was shown to be active against chloroquine sensitive and resistant strains of Plasmodium falciparum 52 , the causative agent of malaria. 1,3-diarylureas have two available cyclic rings that can be readily substituted by various functional groups, allowing the synthesis of several improved compounds 53 . ...
Some 1,3-diarylureas and 1-((1,4-trans)−4-aryloxycyclohexyl)−3-arylureas (cHAUs) activate heme- regulated kinase causing protein synthesis inhibition via phosphorylation of the eukaryotic translation initiation factor 2 (eIF2) in mammalian cancer cells. To evaluate if these agents have potential to inhibit trypanosome multiplication by also a ecting the phosphorylation of eIF2 alpha subunit (eIF2α), we tested 25 analogs of 1,3-diarylureas and cHAUs against Trypanosoma cruzi, the agent of Chagas disease. One of them (I-17) presented selectivity close to 10-fold against the insect replicative forms and also inhibited the multiplication of T. cruzi inside mammalian cells with an EC50 of 1–3 μM and a selectivity of 17-fold. I-17 also prevented replication of African trypanosomes (Trypanosoma brucei bloodstream and procyclic forms) at similar doses. It caused changes in the T. cruzi morphology, arrested parasite cell cycle in G1 phase, and promoted phosphorylation of eIF2α with a robust decrease in ribosome association with mRNA. The activity against T. brucei also implicates eIF2α phosphorylation, as replacement of WT-eIF2α with a non-phosphorylatable eIF2α, or knocking down eIF2 protein kinase-3 by RNAi increased resistance to I-17. Therefore, we demonstrate that eIF2α phosphorylation can be engaged to develop trypanosome-static agents in general, and particularly by interfering with activity of eIF2 kinases.
... Isocyante 2e was generated from the m-trifluoromethoxyaniline that was treated with 1,1′carbonyldiimidazole in DMSO. 12 A significant formation of the byproduct, the symmetrical 1,3-bis(3-(trifluoromethoxy)phenyl)urea, in the preparation of 2e complicated the purification of the targeted ureas 3m−q and resulted in low yields (25−30%). ...
Heme-regulated inhibitor (HRI), an eukaryotic translation initiation factor 2 alpha (eIF2 kinase, plays critical roles in cell proliferation, differentiation, adaptation to stress, and hemoglobin disorders. HRI phosphorylates eIF2 that couples cellular signals including the endoplasmic reticulum (ER) stress to translation. We previously identified 1,3-diarylureas and 1-((1,4-trans)-4-aryloxycyclohexyl)-3-arylureas (cHAUs) as specific activators of HRI that trigger the eIF2 phosphorylation arm of ER-stress response as molecular probes for studying HRI biology and its potential as a druggable target. To develop drug-like cHAUs needed for in vivo studies we undertook bioassay guided structure-activity relationship studies and tested them in the surrogate eIF2 phosphorylation and cell proliferation assays. We further evaluated some of these cHAUs in endogenous eIF2 phosphorylation and expression of the transcription factor CHOP protein and mRNA demonstrating significantly improved solubility and/or potencies. These cHAUs are excellent candidates for lead optimization for development of investigational new drugs that potently and specifically activate HRI.
... 9 In recent years, great efforts have been paid to the development of phosgenefree approaches to these compounds. For example, triphosgene, [9][10][11] chloroformate, 12,13 and N,N'carbonyldiimidazole (CDI) 14 have been developed as the substitutes for phosgene. However, low atom economy limits the utility of these approaches. ...
A facile, phosgene-free approach with high atom economy has been developed for the synthesis of N-Aryl-N'-(4-pyridinyl)ureas. With cheap selenium as the catalyst, carbon monoxide (instead of phosgene) as the carbonyl reagent, N-Aryl-N'-(4-pyridinyl)ureas can be obtained in a one-pot manner mostly in moderate to good yields via oxidative cross-carbonylation of 4-Aminopyridine with a variety of aromatic amines in the presence of oxygen under atmospheric pressure. The mechanism for the synthesis of N-Aryl-N'-(4-pyridinyl)ureas is also proposed.
... N,N=-Diarylureas display a broad spectrum of biological activities and have been investigated for their potential use for tuberculosis (8), malaria (9), HIV (10), immunology (11), and, most extensively, oncology (12). ...
There is an unmet need to discover and develop novel antischistosomal drugs. As exemplified by MMV665852, N,N'-diarylureas have recently emerged as a promising antischistosomal chemotype. In this study, we evaluated the structure-activity relationship of 46 commercially available analogs of MMV665852 on newly transformed schistosomula (NTS) and adult Schistosoma mansoni in vitro. Active compounds were evaluated with a cytotoxicity assay, in silico calculations, metabolic stability studies, and in vivo with mice harboring adult S. mansoni. Of the 46 compounds tested at 33.3 μM, 13 and 14 compounds killed NTS and adult worms within 72 hours, respectively. Nine compounds had IC90 values ≤ 10 μM against adult worms, and a selectivity index ≥ 2.8. The physicochemical properties and permeation through an artificial membrane indicated good to moderate intestinal absorption for these nine compounds. Their metabolic stability was ranging between low and high. Despite satisfactory in vitro results and in silico predictions, only one compound resulted in a statistically significant worm burden reduction (66%) after a single oral dose of 400 mg/kg to S. mansoni-infected mice. Worm burden reductions of 0-43% were observed for the remaining eight compounds tested. In conclusion, several analogs of N,N' -diarylurea MMV665852 had high efficacy against S. mansoni in vitro, and favorable physicochemical properties for permeation through the intestinal wall. To counteract the low efficacy in the mouse model, further investigations should focus on identifying compounds with improved solubility and pharmacokinetic properties.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
... Artemisinin-resistant strains are now also beginning to emerge. 2 In 2007, the Bill and Melinda Gates Foundation supported by other global health organizations initiated a malaria eradication agenda; 2 the combination of resistance and the eradication agenda means that there remains an urgent need for new antimalarial medicines. Among several compounds under development, tafenoquine (7), an analogue of primaquine that originated from the Walter Reed Army Institute of Research, is an 8-aminoquinoline being developed by GSK in conjunction with Medicines for Malaria Venture as a radical cure of P. vivax. ...
Rapid triaging of three series of related hits selected from the Tres Cantos Anti-Malarial Set (TCAMS) are described. A triazolopyrimidine series was deprioritized due to delayed inhibition of parasite growth. A lactic acid series has derivatives with IC50 < 500 nM in a standard Plasmodium falciparum in vitro whole cell assay (Pf assay) but shows half-lives of < 30 min in both human and murine microsomes. Compound 19, from a series of cyclopropyl carboxamides, is a highly potent in vitro inhibitor of P. falciparum (IC50 = 3 nM) and has an oral bioavailability of 55% in CD-1 mice and an ED90 of 20 mg/kg after oral dosing in a nonmyelo-depleted P. falciparum murine model.
... The pharmacophore differs from that constructed by Zhang et al. which contained 2-3 hydrophobic features and 2-3 hydrogen bond acceptors. 25 Not surprisingly, the 3 most active diaryl ureas from the paper by Zhang et al. failed to map to our pharmacophore; most likely, the 4-aminoquinaldine-derived diaryl ureas present different features than the triclosan-derived diaryl ureas. Distinctions in the arrangement of hydrophobic and hydrogen bonding features in the diaryl ureas from Zhang et al. and in this study may enable these molecules to target different proteins in Plasmodium falciparum. ...
Exploration of triclosan analogs has led to novel diaryl ureas with significant potency against in vitro cultures of drug-resistant and drug-sensitive strains of the human malaria parasite Plasmodium falciparum. Compound 18 demonstrated EC(50) values of 37 and 55nM versus in vitro cultured parasite strains and promising in vivo efficacy in a Plasmodium berghei antimalarial mouse model, with >50% survival at day 31 post-treatment when administered subcutaneously at 256mg/kg. This series of compounds provides a chemical scaffold of novel architecture, as validated by cheminformatics analysis, to pursue antimalarial drug discovery efforts.
In the current report, we introduce a simple, mild efficient and green protocol for N-formylation and N-acetylation of anilines using formamide, formic acid, and acetic acid as inexpensive, nontoxic, and easily available starting materials just with heating along stirring in [ChCl][ZnCl2]2 as a durable, reusable deep eutectic solvent (DES), which acts as a dual catalyst and solvent system to produce a wide range of formanilides and acetanilides. Also, a variety of unsymmetrical urea derivatives were synthesized by the reaction of phenyl isocyanate with a range of amine compounds using this benign DES in high to excellent yields. [ChCl][ZnCl2]2 showed good recycling and reusability up to four runs without considerable loss of its catalytic activity.
Cancer and antibiotic-resistant bacterial infections are significant global health challenges. The resistance developed in cancer treatments intensifies therapeutic difficulties. In addressing these challenges, this study synthesised a series of N,N′-dialkyl urea derivatives containing methoxy substituents on phenethylamines. Using isocyanate for the efficient synthesis yielded target products 14–18 in 73–76% returns. Subsequently, their antibacterial and anticancer potentials were assessed. Cytotoxicity tests on cancer cell lines, bacterial strains, and a healthy fibroblast line revealed promising outcomes. All derivatives demonstrated robust antibacterial activity, with MIC values ranging from 0.97 to 15.82 µM. Notably, compounds 14 and 16 were particularly effective against the HeLa cell line, while compounds 14, 15, and 17 showed significant activity against the SH-SY5Y cell line. Importantly, these compounds had reduced toxicity to healthy fibroblast cells than to cancer cells, suggesting their potential as dual-functioning agents targeting both cancer and bacterial infections.
The synthesis and evaluation of twenty six new phenylurea substituted 2,4-diamino-pyrimidines against Plasmodium falciparum (Pf) 3D7 are reported. Compounds were prepared to improve both anti-malarial activity and selectivity of the series previously reported by our group. Additional properties have been determined to assess their potential as anti-malarial leads including; HepG2 cytotoxicity, solubility, permeability, and lipophilicity, as well as in vitro stability in human and rat microsomes. We also assess their inhibition profile against a diverse set of 10 human kinases. Molecular docking, cheminformatics and bioinformatics analyses were also undertaken. Compounds 40 demonstrated the best anti-malarial activity at Pf 3D7 (0.09 μM), good selectivity with respect to mammalian cytotoxicity (SI = 54) and low microsomal clearance. Quantitative structure activity relationship (QSAR) analyses point to lipophilicity being a key driver of improved anti-malarial activity. The most active compounds in the series suffered from high lipophilicity, poor aqueous solubility and low permeability. The results provide useful information to guide further chemistry iterations.
An efficient and convenient Rh(III)-catalyzed double aryl C(sp2)-H bond and N-H activation and annulation reaction is reported for the synthesis of indolo[2,1-a]isoquinolines in the presence of the Cu(OAc)2 oxidant under heating conditions. Distinct from previous works with other arylamine donors, one molecule of 1,3-diarylurea can serve as a precursor of two molecules of arylamine in the reaction with diaryl-substituted alkynes.
Potentially biologically active urea derivatives have been prepared in an efficient one-pot procedure from 1,2,3,4-tetrahydronaphthalene-2-carboxylic acids and characterized via several spectroscopy techniques. Ideal reaction times and temperatures, as well as the absence of metal catalysts and time-consuming and expensive purification chromatographic conditions, allowed the products to be in good yield. The obtained unsymmetrical urea derivatives in an economical and efficient synthetic methodology would be of great interest to be used for potential applications related to drug design, pharmaceutical, and medicinal chemistry.
We now describe the physicochemical profiling, in vitro ADME, and antiparasitic activity of eight N,N'-diarylureas to assess their potential as a broad-spectrum antiprotozoal chemotype. Chromatographic LogD7.4 values ranged from 2.5 to 4.5; kinetic aq. solubilities were ≤6.3 μg/mL, and plasma protein binding ranged from 95 to 99%. All of the compounds had low intrinsic clearance values in human, but not mouse, liver microsomes. Although no N,N'-diarylurea had submicromolar potency against Trypanosoma cruzi, two had submicromolar potencies against Toxoplasma gondii and Trypanosoma brucei rhodesiense, and five had submicromolar potencies against Leishmania donovani. Plasmodium falciparum appeared to be the most susceptible to growth inhibition by this compound series. Most of the N,N'-diarylureas had antiprotozoal selectivities ≥10. One N,N'-diarylurea had demonstrable activity in mouse models of malaria and toxoplasmosis.
The reaction of an alkyl or aryl isocyanates with some primary amines in acetonitrile at room temperature afforded the corresponding alkyl- and aryl-urea derivatives. All the prepared urea compounds have been elucidated by FTIR, NMR, and elemental analysis. The compounds 1 and 3 were confirmed by single-crystal X-ray diffraction. The 4-tolylsulfonyl isocyanate reacted with the aryl amines 1, 2, 3, and 2,4-dichloroaniline to afford the corresponding sulfonylurea derivatives 5–8. Likewise, the reaction of the isocyanates with 2,4-dichloroaniline, 5-methyl isoxazole-3-amine, and 2-aminothiazole derivatives gave the corresponding urea derivatives 9–17. All the prepared compounds 5–17 were tested in vitro as anti-microbial and anti-HepG2 agents. Moreover, analyzing gene expression of TP53-exon4 and TP53-exon7, DNA damage values, and DNA fragmentation percentages have been discussed. The compounds 5 and 8 recorded the highest activity against the tested microbial strains with maximum activity against C. albicans (50 mm) and B. mycoides (40 mm), respectively. The compounds 5 inhibited the growth of E. coli, S. aureus, and C. Albicans at the MIC level of 0.0489 µM, while the compound 8 was able to inhibit the visible growth of E. coli and C. albicans at MIC value of 3.13 µM and S. aureus at 0.3912 µM. In the same line, compound 5 showed the best cytotoxic activity against the HepG2 cell line (IC50 = 4.25 µM) compared to 5 fluorouracil with IC50 = 316.25 µM. Expression analysis of liver cancer related to a gene including TP53-exon4 and TP53-exon7 was used in HepG2 Liver cancer cell lines using RT-qPCR. The expression values of TP53-exon4 and TP53-exon7 genes were decreased. The DNA damage values and DNA fragmentation percentages were increased significantly (P<0.01) in the treated HepG2 (5) sample compared with the negative control. Docking studies were performed for the synthetic compounds against 2 bacterial proteins (DNA gyrase subunit B, and penicillin binding protein 1a) that are known targets for some antibiotics, and one cell division protein kinase 2 (CDK2) as target for anticancer drugs.
Triclocarban (TCC), a broad-spectrum lipophilic antimicrobial agent, is a diarylurea derivative that has been used for more than 60 years as a major ingredient of toys, clothing, food packaging materials, food industry floors, medical supplies and especially of personal care products, such as soaps, toothpaste and shampoo. In September 2016, the U.S. FDA banned nineteen antimicrobial ingredients, including TCC, in over-the-counter consumer antiseptic wash products, due to their toxicity. Withdrawal of TCC has prompted efforts to search for new antimicrobial compounds. In this paper, we present the synthesis and biological evaluation, as antibiotic and non-cytotoxic agents, of a series of diarylureas, analogues of TCC. These compounds are characterized by an intriguingly simple chemistry and can be easily synthesized. Among the synthesized compounds, 1ab and 1bc emerge as the most interesting compounds as they show the same activity of TCC (MIC = 16 µg/mL) against Staphylococcus aureus, and a higher activity than TCC against Enterococcus faecalis (MIC = 32 µg/mL versus MIC = 64 µg/mL). Moreover, 1ab and 1bc show no cytotoxicity towards the human mammary epithelial cells MCF-10A and embryonic kidney epithelial cells Hek-293, in opposition to TCC, which exhibits a marked cytotoxicity on the same cell lines and shows a good antitumor activity on a panel of cell lines tested.
An unprecedented base promoted domino approach has been developed for the synthesis of pyridin-2-yl urea derivatives via the reaction of 2-aminopyridinium salts and arylamines. The developed strategy tolerated a wide range of functional groups and afforded pyridin-2-yl ureas in moderate to good yields. The reaction was postulated to involve tandem cyclization, intermolecular nucleophilic addition, ring opening, and demethylation.
An efficient, economical and phosgene-free procedure for the synthesis of N-aryl-N’-2-thiazolylureas is reported. With cheap and recyclable nonmetal selenium instead of noble metals as the catalyst, carbon monoxide instead of virulent phosgene as the carbonylation agent, the selenium-catalyzed carbonylation reaction of 2-aminothiazole can proceed smoothly in one-pot manner with a variety of nitro aromatics in the presence of triethylamine to afford the desired N-aryl-N’-2-thiazolylureas mostly in moderate to good yields. Selenium catalyst can be easily recovered due to its phase-transfer catalytic ability and reused without any significant degradation of its catalytic performance.
With the aim to help drug discovery against dengue virus (DENV), a fragment-based drug design approach was applied to identify ligands targeting a main component of DENV replication complex: the NS5 AdoMet-dependent mRNA methyltransferase (MTase) domain, playing an essential role in the RNA capping process. Herein, we describe the identification of new inhibitors developed using fragment-based, structure-guided linking and optimization techniques. Thermal-shift assay followed by a fragment-based X-ray crystallographic screening lead to the identification of three fragment hits binding DENV MTase.
A novel solvent- and halide-free atom-economical synthesis of practically useful pyridine-2-yl substituted ureas utilizes easily accessible or commercially available pyridine N-oxides (PyO) and dialkylcyanamides. The observed C–H functionalization of PyO is suitable for the good-to-high yielding synthesis of a wide range of pyridine-2-yl substituted ureas featuring electron donating and electron withdrawing, sensitive, or even fugitive functional groups at any position of the pyridine ring (63–92%; 19 examples). In the cases of 3-substituted PyO, the C–H functionalization occurs regioselectively providing a route for facile generation of ureas bearing a 5-substituted pyridine-2-yl moiety.
A scalable and facile synthetic process for N-(pyridin-4-yl)piperazine-1-carboxamide hydrochloride, a novel Rho kinase inhibitor with an unsymmetrical urea structure currently under investigation for the treatment of central nervous system disorders, was established. After optimisation of the reaction conditions, N-(pyridin-4-yl)piperazine-1-carboxamide hydrochloride was synthesised from 4-aminopyridine and N,N'-carbonyldiimidazole through acylation, deprotection and salt formation. This new procedure affords the product in 53% overall yield with high purity and it can be easily scaled up for production.
Quinoline-containing compounds, such as quinine and chloroquine, have a long-standing history as potent antimalarial agents. However, the increasing resistance of the Plasmodium parasite against these drugs and the lack of licensed malaria vaccines have forced chemists to develop synthetic strategies toward novel biologically active molecules. A strategy that has attracted considerable attention in current medicinal chemistry is based on the conjugation of two biologically active molecules into one hybrid compound. Since quinolines are considered to be priviliged antimalarial building blocks, the synthesis of quinoline-containing antimalarial hybrids has been elaborated extensively in recent years. This review provides a literature overview of antimalarial hybrid molecules containing a quinoline core, covering publications between 2009 and 2014.
Thirty symmetrical diaryl urea derivatives were synthesised in moderate to excellent yields from arylamine and triphosgene with triethylamine as a reducing agent for the intermediate, isocyanate. It was significant that part of the products could be collected in almost quantitative
yield without column chromatography. The procedure under mild reaction conditions was tolerant of a wide range of functional groups. The structures of the compounds were determined by NMR, MS and X-ray crystallographic analyses.
A new series of C- linked phenyl butenonyl glycosides bearing ureidyl(thioureidyl) and sulfonamidyl moieties in the phenyl rings were designed, synthesized and evaluated for their in vitro antimalarial activities against Plasmodium falciparum 3D7 (CQ sensitive) and K1 (CQ resistant) strains. Among all the compounds screened the C- linked phenyl butenonyl glycosides bearing sulfonamidyl moiety (5a) and ureidyl moiety in the phenyl ring (7d and 8c) showed promising antimalarial activities against both 3D7 and K1 strains with IC50 values in µM range and low cytotoxicity offering new HITS for further exploration.
A simple and readily available PdCl2 catalyzed carbamate synthesis method via isocyanate generation and application in situ has been developed. This chemistry provides an efficient and practical approach to synthesize carbamates from simple organic azides, CO atmosphere and alcohols. The broad scope, mild and neutral conditions, and only N2 as the byproduct make this transformation very useful. Moreover, simple examples of modification of bioactive molecules and construction of macrocycles were achieved through this protocol.
A facile synthesis of unsymmetrical N,N'-diarylureas is described. The utilization of the Pd-catalyzed arylation of ureas enables the synthesis of an array of diarylureas in good to excellent yields from benzylurea via a one-pot arylation-deprotection protocol, followed by a second arylation.
Protein kinases (PKs) are prime targets for drug discovery in a variety of diseases, including cancer and neurodegenerative pathologies. The characterisation of the kinome of the human malaria parasite Plasmodium falciparum has revealed profound divergences, at several levels, between PKs of the parasite and those of its host. Here, the authors review the major issues and recent advances regarding the development of Plasmodium-selective PK inhibitors, with emphasis on target identification and validation, and on structure-based design. The authors also discuss the possibility of interfering with: i) Plasmodium PKs regulating transmission to the mosquito vector; and ii) host PKs that may be required for parasite survival.
Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border, historically a site of emerging antimalarial-drug resistance.
In two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram. We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance.
We studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate-mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P=0.31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups.
P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. (ClinicalTrials.gov number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.)
During the intraerythrocytic stage of infection, the malaria parasite Plasmodium falciparum digests most of the host cell hemoglobin. Hemoglobin degradation occurs in the acidic digestive vacuole and is essential for the survival of the parasite. Two aspartic proteases, plasmepsins I and II, have been isolated from the vacuole and shown to make the initial cleavages in the hemoglobin molecule. We have studied the biosynthesis of these two enzymes. Plasmepsin I is synthesized and processed to the mature form soon after the parasite invades the red blood cell, while plasmepsin II synthesis is delayed until later in development. Otherwise, biosynthesis of the plasmepsins is identical. The proplasmepsins are type II integral membrane proteins that are transported through the secretory pathway before cleavage to the soluble form. They are not glycosylated in vivo, despite the presence of several potential glycosylation sites. Proplasmepsin maturation appears to require acidic conditions and is reversibly inhibited by the tripeptide aldehydes N-acetyl-L-leucyl-L-leucyl-norleucinal and N-acetyl-L-leucyl-L-leucyl-methional. These compounds are known to inhibit cysteine proteases and the chymotryptic activity of proteasomes but not aspartic proteases. However, proplasmepsin processing is not blocked by other cysteine protease inhibitors, nor by the proteasome inhibitor lactacystin. Processing is also not blocked by aspartic protease inhibitors. This inhibitor profile suggests that unlike most other aspartic proteases, proplasmepsin maturation may not be autocatalytic in vivo, but instead could require the action of an unusual processing enzyme. Compounds that block processing are expected to be potent antimalarials.
Hemoglobin degradation in intraerythrocytic malaria parasites is a vast process that occurs in an acidic digestive vacuole. Proteases that participate in this catabolic pathway have been defined. Studies of protease biosynthesis have revealed unusual targeting and activation mechanisms. Oxygen radicals and heme are released during proteolysis and must be detoxified by dismutation and polymerization, respectively. The quinoline antimalarials appear to act by preventing sequestration of this toxic heme. Understanding the disposition of hemoglobin has allowed identification of essential processes and metabolic weakpoints that can be exploited to combat this scourge of mankind.
Malarial parasites rely on aspartic proteases called plasmepsins to digest hemoglobin during the intraerythrocytic stage. Plasmepsins from Plasmodium falciparum and Plasmodium vivax have been cloned and expressed for a variety of structural and enzymatic studies. Recombinant plasmepsins possess kinetic similarity to the native enzymes, indicating their suitability for target-based antimalarial drug development. We developed an automated assay of P. falciparum plasmepsin II and P. vivax plasmepsin to quickly screen compounds in the Walter Reed chemical database. A low-molecular-mass (346 Da) diphenylurea derivative (WR268961) was found to inhibit plasmepsins with a K(i) of 1 to 6 microM. This compound appears to be selective for plasmepsin, since it is a poor inhibitor of the human aspartic protease cathepsin D (K(i) greater than 280 microM). WR268961 inhibited the growth of P. falciparum strains W2 and D6, with 50% inhibitory concentrations ranging from 0.03 to 0.16 microg/ml, but was much less toxic to mammalian cells. The Walter Reed chemical database contains over 1,500 compounds with a diphenylurea core structure, 9 of which inhibit the plasmepsins, with K(i) values ranging from 0.05 to 0.68 microM. These nine compounds show specificity for the plasmepsins over human cathepsin D, but they are poor inhibitors of P. falciparum growth in vitro. Computational docking experiments indicate how diphenylurea compounds bind to the plasmepsin active site and inhibit the enzyme.
Malaria, caused by the parasitic protist Plasmodium falciparum, represents a major public health problem in the developing world. The P. falciparum genome has been sequenced, which provides new opportunities for the identification of novel drug targets. Eukaryotic protein kinases (ePKs) form a large family of enzymes with crucial roles in most cellular processes; hence malarial ePKS represent potential drug targets. We report an exhaustive analysis of the P. falciparum genomic database (PlasmoDB) aimed at identifying and classifying all ePKs in this organism.
Using a variety of bioinformatics tools, we identified 65 malarial ePK sequences and constructed a phylogenetic tree to position these sequences relative to the seven established ePK groups. Predominant features of the tree were: (i) that several malarial sequences did not cluster within any of the known ePK groups; (ii) that the CMGC group, whose members are usually involved in the control of cell proliferation, had the highest number of malarial ePKs; and (iii) that no malarial ePK clustered with the tyrosine kinase (TyrK) or STE groups, pointing to the absence of three-component MAPK modules in the parasite. A novel family of 20 ePK-related sequences was identified and called FIKK, on the basis of a conserved amino acid motif. The FIKK family seems restricted to Apicomplexa, with 20 members in P. falciparum and just one member in some other Apicomplexan species.
The considerable phylogenetic distance between Apicomplexa and other Eukaryotes is reflected by profound divergences between the kinome of malaria parasites and that of yeast or mammalian cells.
Plasmodium falciparum is the causative agent of the most serious and fatal malarial infections, and it has developed resistance to commonly employed
chemotherapeutics. The de novo pyrimidine biosynthesis enzymes offer potential as targets for drug design, because, unlike the host, the parasite does not
have pyrimidine salvage pathways. Dihydroorotate dehydrogenase (DHODH) is a flavin-dependent mitochondrial enzyme that catalyzes
the fourth reaction in this essential pathway. Coenzyme Q (CoQ) is utilized as the oxidant. Potent and species-selective inhibitors
of malarial DHODH were identified by high-throughput screening of a chemical library, which contained 220,000 drug-like molecules.
These novel inhibitors represent a diverse range of chemical scaffolds, including a series of halogenated phenyl benzamide/naphthamides
and urea-based compounds containing napthyl or quinolinyl substituents. Inhibitors in these classes with IC50 values below 600 nm were purified by high pressure liquid chromatography, characterized by mass spectroscopy, and subjected to kinetic analysis
against the parasite and human enzymes. The most active compound is a competitive inhibitor of CoQ with an IC50 against malarial DHODH of 16 nm, and it is 12,500-fold less active against the human enzyme. Site-directed mutagenesis of residues in the CoQ-binding site
significantly reduced inhibitor potency. The structural basis for the species selective enzyme inhibition is explained by
the variable amino acid sequence in this binding site, making DHODH a particularly strong candidate for the development of
new anti-malarial compounds.
Diarylurea (DAU) compounds, particularly species composed of a heteroaryl ring system conjugated through a urea linkage to a substituted arene, were previously identified by the screening of a diverse chemical library to be active against the insulin growth factor receptor (IGF-1R). DAU compounds 4{a,b} were synthesized in parallel by the coupling of aryl amines 2{a} with aryl isocyanates 3{b}. Preparative RP-HPLC purification was found necessary to remove an impurity 5{b}, the symmetric urea resulting from the hydrolytic degradation of aryl isocyanates. Two libraries of DAU compounds were prepared to perform preliminary optimization of the two-ring systems for inhibitory activity against IGF-1R. In the first library, we explored a series of heteroaryl ring systems and found the 4-aminoquinaldine ring system to be optimal among those evaluated. The second library fixed the 4-aminoquinaldine ring system and we evaluated a series of substituted arenes conjugated to it. Overall, eight compounds based on the 4-aminoquinaldine heteroaryl system were found to have moderate activity against IGF-1R with IC(50) values better than 40 microM.
Protein kinases (PKs) are prime targets for drug discovery in a variety of diseases, including cancer and neurodegenerative pathologies. The characterisation of the kinome of the human malaria parasite Plasmodium falciparum has revealed profound divergences, at several levels, between PKs of the parasite and those of its host. Here, the authors review the major issues and recent advances regarding the development of Plasmodium-selective PK inhibitors, with emphasis on target identification and validation, and on structure-based design. The authors also discuss the possibility of interfering with: i) Plasmodium PKs regulating transmission to the mosquito vector; and ii) host PKs that may be required for parasite survival.
A total of 80 new 2-methyl-6-ureido-4-quinolinamides were synthesized and evaluated for their antimalarial activity. Several analogs elicited the antimalarial effect at MIC of 0.25 mg/mL against the chlooquine-sensitive P. falciparum strain. The IC(50) values of the active compounds were observed to be in ng/mL range and two of the analogs have better IC(50) value than the standard chloroquine. In the in vivo assay against mdr CQ resistant P. yoelii N67/P. yoelii nigeriensis, however, none of the compound showed complete suppression of parasitemia on day 7. One of the compounds displayed significant antibacterial effect against several strains of bacteria and was many-fold better than the standard drug gentamicin.
Synthesis of new 6-ureido-4-anilinoquinazolines have been accomplished and their in vitro antimalarial activity against chloroquine-sensitive P. falciparum have been examined. Out of 64 compounds evaluated, the IC(50) of 16 compounds which have displayed MIC of 0.25 microg/mL were also recorded. One of the compounds (24 g) had IC(50) value of 2.27 ng/mL which was equipotent to the standard drug chloroquine used in the bioassay. The in vivo evaluation of a few compounds among the series led to discovery of one analog (30 g) displaying 40% curative activity (28 days) against mdr P. yoeillinigeriensis at an oral dose of 100 mg/kg x 4 days.
The malarial parasite Plasmodium falciparum can only synthesize pyrimidine nucleotides via the de novo pathway which is therefore a suitable target for development of antimalarial drugs. New assay procedures have been developed using high-pressure liquid chromatography (HPLC) which enable concurrent measurement of pyrimidine intermediates in malaria. Synchronized parasites growing in erythrocytes were pulse-labeled with [14C]bicarbonate at 6-h intervals around the 48-h asexual life cycle. Analysis of malarial extracts by HPLC showed tht incorporation of [14C]bicarbonate into pyrimidine nucleotides was maximal during the transition from trophozoites to schizonts. The reaction, N-carbamyl-L-aspartate-->L-dihydroorotate (CA-asp-->DHO) catalyzed by malarial dihydroorotase is inhibited by L-6-thiodihydroorotate (TDHO) in vitro (Ki = 6.5 microM), and TDHO, as the free acid or methyl ester, induces a major accumulation of CA-asp in malaria. Atovaquone, a naphthoquinone, is a moderate inhibitor of dihydroorotate dehydrogenase in vitro (Ki = 27 microM) but induces major accumulations of CA-asp and DHO. Pyrazofurin induces accumulation of orotate and orotidine in malaria, consistent with inhibition of orotidine 5'-monophosphate (OMP) decarboxylase with subsequent dephosphorylation of the OMP accumulated. Although TDHO, atovaquone, and pyrazofurin arrest the growth of P. falciparum, only moderate decreases in UTP, CTP, and dTTP were observed. 5-Fluoroorotate also arrests the growth of P. falciparum with major accumulations of 5-fluorouridine mono-, di-, and triphosphates and the most significant inhibition of de novo biosynthesis of pyrimidine nucleotides.
All parasitic protozoa contain multiple proteases, some of which are attracting attention as drug targets. Aspartic proteases are already the targets of some clinically useful drugs (e.g. chemotherapy of HIV infection) and a variety of factors make these enzymes appealing to those seeking novel antiparasite therapies. This review provides a critical analysis of the current knowledge on Plasmodium aspartic proteases termed plasmepsins, proposes a definitive nomenclature for this group of enzymes, and compares these enzymes with aspartic proteases of humans and other parasitic protozoa. The present status of attempts to obtain specific inhibitors of the parasite enzymes that will be useful as drugs is outlined and suggestions for future research priorities are proposed.
The high throughput in silico screening of a virtual library into the structure of the P. falciparum lactate dehydrogenase (LDH) with the 4SCan technology yielded a series of biphenyl urea compounds. These were chemically optimized to a new structural class of potent antimalarial agents. The compounds did not inhibit plasmodium LDH enough to fully explain their potency. Therefore we conclude that an unknown mode of action may be the cause of the antimalarial activity.
Protein kinases are central to regulation of cellular signaling in the eukaryotes. Well-conserved and lineage-specific protein kinases have previously been identified from various completely sequenced genomes of eukaryotes. The current work describes a genome-wide analysis for protein kinases encoded in the Plasmodium falciparum genome. Using a few different profile matching methods, we have identified 99 protein kinases or related proteins in the parasite genome. We have classified these kinases into subfamilies and analyzed them in the context of noncatalytic domains that occur in these catalytic kinase domain-containing proteins. Compared to most eukaryotic protein kinases, these sequences vary significantly in terms of their lengths, inserts in catalytic domains, and co-occurring domains. Catalytic and noncatalytic domains contain long stretches of repeats of positively charged and other polar amino acids. Various components of the cell cycle, including 4 cyclin-dependent kinase (CDK) homologues, 2 cyclins, 1 CDK regulatory subunit, and 1 kinase-associated phosphatase, are identified. Identification of putative mitogen-activated protein (MAP) Kinase and MAP Kinase Kinase of P. falciparum suggests a new paradigm in the highly conserved signaling pathway of eukaryotes. The calcium-dependent kinase family, well represented in P. falciparum, shows varying domain combinations with EF-hands and pleckstrin homology domains. The analysis reveals a new subfamily of protein kinases having limited sequence similarity with previously known subfamilies. A new transmembrane kinase with 6 membrane-spanning regions is identified. Putative apicoplast targeting sequences have been detected in some of these protein kinases, suggesting their export to the apicoplast.
Phenylurenyl chalcone derivatives have been synthesized and tested as inhibitors of in vitro development of a chloroquine-resistant strain of Plasmodium falciparum, activity of the cysteine protease falcipain-2, in vitro globin hydrolysis, beta-hematin formation, and murine Plasmodium berghei malaria. The most active antimalarial compound was 1-[3'-N-(N'-phenylurenyl)phenyl]-3(3,4,5-trimethoxyphenyl)-2-propen-1-one 49, with an IC(50) of 1.76 microM for inhibition of P. falciparum development. Results suggest that chalcones exert their antimalarial activity via multiple mechanisms.
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.
Atovaquone is a substituted hydroxynaphthoquinone that is used therapeutically for treating Plasmodium falciparum malaria, Pneumocystis jirovecii pneumonia and Toxoplasma gondii toxoplasmosis. It is thought to act on these organisms by inhibiting parasite and fungal respiration by binding to the cytochrome bc1 complex. The recent, growing failure of atovaquone treatment and increased mortality of patients with malaria or Pneumocystis pneumonia has been linked to the appearance of mutations in the cytochrome b gene. To better understand the molecular basis of drug resistance, we have developed the yeast and bovine bc1 complexes as surrogates to model the molecular interaction of atovaquone with human and resistant pathogen enzymes.
World Health Organization
WHO Malarial Report 2008. World Health Organization;
Hemoglobin metabolism in the malaria parasite Plasmodium falciparum
- S E Francis
- D J Sullivan
- Jr
- D E Goldberg
Francis, S. E.; Sullivan, D. J., Jr.; Goldberg, D. E. Hemoglobin
metabolism in the malaria parasite Plasmodium falciparum.
Annu. Rev. Microbiol. 1997, 51, 97-123.