Richard R. Tidwell's research while affiliated with University of North Carolina at Chapel Hill and other places
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Publications (234)
Mutations in the Trypanosoma brucei aquaporin AQP2 are associated with resistance to pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively selected for increased pore size from a common ancestor aquaporin. We demonstrate that TbAQP2’s unique architecture permits pentamidine permeation through its central pore and show how s...
Mutations in the Trypanosoma brucei aquaporin AQP2 are associated with resistance to pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively selected for increased pore size from a common ancestor aquaporin. We demonstrate that TbAQP2’s unique architecture permits pentamidine permeation through its central pore and show how s...
Mutations in the Trypanosoma brucei aquaporin AQP2 are associated with resistance to pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively selected for increased pore size from a common ancestor aquaporin. We demonstrate that TbAQP2's unique architecture permits pentamidine permeation through its central pore and show how s...
Mutations in the Trypanosoma brucei aquaporin AQP2 are associated with resistance to pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively selected for increased pore size from a common ancestor aquaporin. We demonstrate that TbAQP2's unique architecture permits pentamidine permeation through its central pore and show how s...
Five bis-arylimidamides were assayed as anti- T.cruzi agents using in vitro , in silico and in vivo approaches. All were considered no PAINS, have favorable pharmacokinetic landscape, were active against trypomastigotes and intracellular forms but combined with benznidazole gave no interaction. The most selective (28SMB032) moved to in vivo led to...
African
Animal Trypanosomosis (AAT) is caused by the tsetse-transmitted protozoans, Trypanosoma congolense and T. vivax, leading to huge agricultural losses throughout sub-Saharan Africa. Three drugs are available to treat Nagana in cattle (diminazene diaceturate, homidium- and isometamidium chloride). With increasing reports of drug-resistant popu...
Background:
The failing heart exhibits an increased arrhythmia susceptibility that is often attributed to action potential (AP) prolongation due to significant ion channel remodeling. IK1 has been reported to be reduced, but its contribution to shaping the AP waveform and cell excitability in the failing heart remains unclear.
Objective:
To defi...
A previous publication from this lab (Patrick, et al. Bioorg. Med. Chem. 2016, 24 , 2451 - 2465 ) explored the antitrypanosomal activities of novel derivatives of 2-(2-benzamido)ethyl-4-phenylthiazole (1), which had been identified as a hit against Trypanosoma brucei, the causative agent of human African trypanosomiasis. While a number of these com...
2-(2-Benzamido)ethyl-4-phenylthiazole (1) was one of 1035 molecules (grouped into 115 distinct scaffolds) found to be inhibitory to Trypanosoma brucei, the pathogen causing human African trypanosomiasis, at concentrations below 3.6μM and non-toxic to mammalian (Huh7) cells in a phenotypic high-throughput screen of a 700,000 compound library perform...
Arylimidamides (AIA) showed considerable biological activity against intracellular pathogens, including Trypanosoma cruzi. Presently, the analysis of twelve novel bis-AIAs and two mono-AIAs was performed against different strains of T. cruzi in vitro and in vivo. The most active was m-terphenyl bis-AIA 35DAP073, with EC50 value of 0.5 μM on trypoma...
Background
Sleeping sickness (human African trypanosomiasis [HAT]) is caused by protozoan parasites and characterized by a chronic progressive course, which may last up to several years before death. We conducted two Phase 2 studies to determine the efficacy and safety of oral pafuramidine in African patients with first stage HAT.
Methods
The Phas...
CONSORT checklist.
(DOC)
Background
Sleeping sickness (human African trypanosomiasis [HAT]) is a neglected tropical disease with limited treatment options that currently require parenteral administration. In previous studies, orally administered pafuramidine was well tolerated in healthy patients (for up to 21 days) and stage 1 HAT patients (for up to 10 days), and demonst...
Author Summary
Treatment of human African trypanosomiasis (HAT, sleeping sickness) suffers from a shortage of medicines that are both effective, especially against the second (late) stage of the disease, and safe for patients. The development of new HAT medicines also has been significantly influenced by the perceived need for easily administered o...
African sleeping sickness is a neglected tropical disease transmitted by tsetse flies. New and better drugs are still needed
especially for its second stage, which is fatal if untreated. 28DAP010, a dipyridylbenzene analogue of DB829, is the second
simple diamidine found to cure mice with central nervous system infections by a parenteral route of a...
Chagas disease (CD), a neglected tropical disease caused by Trypanosoma cruzi, remains a serious public health problem in several Latin American countries. The available chemotherapies for CD have limited efficacy and exhibit undesirable side effects. Aromatic diamidines and arylimidamides (AIAs) have shown broad-spectrum activity against intracell...
DB844 (CPD-594-12), N-methoxy-6-{5-[4-(N-methoxyamidino)phenyl]-furan-2-yl}-nicotinamidine, is an oral prodrug that has shown promising efficacy in both mouse and monkey models of second stage human African trypanosomiasis. However, gastrointestinal (GI) toxicity was observed with high doses in a vervet monkey safety study. In the current study, we...
Fifty novel prodrugs and aza-analogues of 3,5-bis(4-amidinophenyl)isoxazole and its derivatives were prepared. Eighteen of the 24 aza-analogues exhibited IC50 values below 25nM against Trypanosoma brucei rhodesiense or Plasmodium falciparum. Six compounds had antitrypanosomal IC50 values below 10nM. Twelve analogues showed similar antiplasmodial ac...
4,4″-Diamidino-m-terphenyl (1) and 36 analogues were prepared and assayed in vitro against T rypanosoma brucei rhodesiense , Trypanosoma cruzi , Plasmodium falciparum , and Leishmania amazonensis . Twenty-three compounds were highly active against T. b. rhodesiense or P. falciparum. Most noteworthy were amidines 1, 10, and 11 with IC50 of 4 nM agai...
Purpose: Atrial fibrillation (AF) is the most common cardiac rhythm disorder. Pharmacological treatment of AF is hampered by ventricular pro-arrhythmia. Modulation of atrium-specific Kir3.x channels, which generate a constitutively active current (IK,ACh-c) after atrial remodeling, could possibly circumvent this problem. However, it is not yet know...
There are no oral drugs for human African trypanosomiasis (HAT, sleeping sickness). A successful oral drug would have the
potential to reduce or eliminate the need for patient hospitalization, thus reducing healthcare costs of HAT. The
development of oral medications is a key objective of the Consortium for Parasitic Drug Development (CPDD). In thi...
Aims In excitable cells, KIR2.x ion-channel-carried inward rectifier current (IK1) is thought to set the negative and stable resting membrane potential, and contributes to action potential repolarization.
Loss- or gain-of-function mutations correlate with cardiac arrhythmias and pathological remodelling affects normal KIR2.x protein levels. No spec...
Drug interference with normal hERG protein trafficking substantially reduces the channel density in the plasma membrane and thereby poses an arrhythmic threat. The chemical substructures important for hERG trafficking inhibition were investigated using pentamidine as a model drug. Furthermore, the relationship between acute ion channel block and co...
DB868 [2,5-bis [5-(N-methoxyamidino)-2-pyridyl] furan], a prodrug of the diamidine DB829 [2,5-bis(5-amidino-2-pyridyl) furan], has demonstrated efficacy in murine models of human African trypanosomiasis. A cross-species evaluation of prodrug bioconversion to the active drug is required to predict the disposition of prodrug, metabolites, and active...
DB289 is the first oral drug shown in clinical trials to have efficacy in treating African trypanosomiasis (African sleeping sickness). Mild liver toxicity was noted but was not treatment limiting. However, development of DB289 was terminated when several treated subjects developed severe kidney injury, a liability not predicted from preclinical te...
Individual monkey concentration-time profiles of DB844 and DB820 in plasma. The monkeys were treated orally with DB844 at 6 mg/kg×14 days, from 28–41 days post infection with T.b. rhodesiense KETRI2537. The insert graph shows the extended profiles up to 28 days post the last daily dose of DB844.
(TIF)
Individual monkey activity/concentration-time profiles of aspartate amino transferase and blood urea nitrogen in plasma. The monkeys were treated with DB844 at 6 mg/kg×14 days, from 28–41 days post infection with T.b. rhodesiense KETRI2537.
(TIF)
Novel drugs to treat human African trypanosomiasis (HAT) are still urgently needed despite the recent addition of nifurtimox-eflornithine combination therapy (NECT) to WHO Model Lists of Essential Medicines against second stage HAT, where parasites have invaded the central nervous system (CNS). The pharmacology of a potential orally available lead...
Short AT base pair sequences that are separated by a small number of GCs are common in eukaryotic parasite genomes. Cell-permeable compounds that bind effectively and selectively to such sequences present an attractive therapeutic approach. Compounds with linked, one or two amidine-benzimidazole-phenyl (ABP) motifs were designed, synthesized, and e...
Dose selection during antiparasitic drug development in animal models and humans traditionally has relied on correlations between plasma concentrations obtained at or below maximally tolerated doses that are efficacious. The objective of this study was to improve the understanding of the relationship between dose and plasma/tissue exposure of the m...
STROBE checklist.
(DOCX)
Author Summary
Because of weak health surveillance infrastructures in poor countries, estimates of the burdens (numbers of infections) of many tropical diseases may be inaccurate. In particular, current estimates for the global burden of Human African Trypanosomiasis (Sleeping Sickness, HAT) vary widely. Most of the reported HAT cases occur in the...
Dicationic diamidines, such as diminazene and pentamidine, are well-studied chemotherapeutic agents with significant activity
against parasitic diseases. The in vitro activities of novel diamidine compounds against the Babesia divergens strains 1903B and 4201 were investigated. The most potent compound, a diphenyl furan, had a 50% inhibitory concen...
Selection of in vitro models that accurately characterize metabolite systemic and hepatobiliary exposure remains a challenge in drug development. In the present study, mechanisms underlying differences in systemic exposure of two active metabolites, furamidine and 2,5-bis (5-amidino)-2-pyridyl furan (CPD-0801), were examined using two hepatic model...
Analogs of the trypanocidal lead compound 1-benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate were prepared to extend the structure-activity relationship in this series of molecules, improve the in vivo antitrypanosomal activity of the lead, and determine whether ester prodrugs are needed to overcome the instability of the dihydroquinolin-6-o...
To develop an oral formulation of amphotericin B (AmB) that is stable at the temperatures of WHO Climatic Zones 3 and 4 (30-43 °C) and to evaluate its efficacy in a murine model of visceral leishmaniasis (VL).
The stability testing of four novel oral lipid AmB formulations composed of mono- and di-glycerides and pegylated esters (iCo-010 to iCo-013...
Pentamidine and its analogs constitute a class of compounds that are known to be active against Plasmodium falciparum, which causes the most dangerous malarial infection. Malaria is a widespread disease known to affect hundreds of millions of people and presents a perceivable threat of spreading. Hence, there is a need for well-defined scaffolds th...
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Aromatic diamidines are potent trypanocides. Pentamidine, a diamidine, has been used for more than 60 years to treat human African trypanosomiasis (HAT); however, the drug must be administered parenterally and is active against first-stage HAT only, prior to the parasites causing neurological deterioration through invasion of the CNS. A major resea...
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Human African trypanosomiasis (HAT), also called African sleeping sickness, is a neglected tropical parasitic disease indigenous to sub-Saharan Africa. Diamidine compounds, including pentamidine and CPD-0801, are potent anti-trypanosomal molecules. The latter is a potential drug in the development at the UNC based Consortium for Parasitic Drug Deve...
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Trypanosoma evansi is an animal pathogenic protozoan, causing a wasting disease called Surra, which is broadly distributed in a wide range of mammalian hosts. Chemotherapy is the most efficient control method, which depends on four drugs. Unfortunately, with the appearance of resistance to these drugs, their effective use is threatened, emphasising...
Trypanosoma cruzi is a parasite that causes Chagas disease, which affects millions of individuals in endemic areas of Latin America. One hundred years after the discovery of Chagas disease, it is still considered a neglected illness because the available drugs are unsatisfactory. Aromatic compounds represent an important class of DNA minor groove-b...
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
The global distribution of leishmaniasis is rapidly expanding into new geographic regions. Dogs are the primary reservoir hosts for human visceral leishmaniasis caused by infection with Leishmania infantum. Natural infections with other Leishmania spp. can occur in dogs, but their role as reservoir hosts for other species of Leishmania is uncertain...
Arylimidamides (AIAs) represent a new class of molecules that exhibit potent antileishmanial activity (50% inhibitory concentration [IC(50)], <1 microM) against both Leishmania donovani axenic amastigotes and intracellular Leishmania, the causative agent for human visceral leishmaniasis (VL). A systematic lead discovery program was employed to char...
To assess the impact of visceral leishmaniasis (VL) on the concentration of amphotericin B (AmB) recovered in the liver and spleen following either intravenous (AmBisome) or oral (iCo-009) AmB administration to mice.
Livers and spleens previously obtained from VL-infected BALB/c mice (following intravenous AmBisome or oral AmB treatments) were anal...
Surra is an animal pathogenic protozoan infection, caused by Trypanosoma evansi, that develops into a fatal wasting disease. Control measures rely on diagnosis and treatment. However, with the continuous emergence of drug resistance, this tactic is failing, and the pressing need for new chemotherapeutic agents is becoming critical. With the introdu...
Novel dicationic triazoles 1-60 were synthesized by the Pinner method from the corresponding dinitriles, prepared via the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The type and the placement of cationic moieties as well as the nature of aromatic substituents influenced in vitro antiprotozoal activities of compounds 1-60 against Trypan...
Aromatic diamidines (ADs) have been recognized as promising antiparasitic agents. Therefore, in the present work, the in vitro trypanocidal effect of 11 ADs upon the relevant clinical forms of Trypanosoma cruzi was evaluated, as well as determining their toxicity to mammalian cells and their subcellular localization.
The trypanocidal effect upon tr...
Forty-eight cationically substituted pentamidine congeners possessing benzofuran rings were synthesized by a copper mediated heteroannulation of substituted o-iodophenols with phenyl acetylenes. Activities of compounds 1-48 against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani and cytotoxicities for mammalian cells...
A series of novel pyridyl analogues 1-18 of antiprotozoal drug 1,5-bis(4-amidinophenoxy)pentane (pentamidine) has been synthesized and tested for in vitro activities against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani, and for cytotoxicity against mammalian cells. Antiprotozoal properties of compounds 1-18 depende...
DB289, [2,5-bis(4-amidinophenyl)furan bis-O-methylamidoxime], is a broad spectrum anti-parasitic compound which has been shown to be effective against malaria in recent clinical trials. DB75, [2,5-bis(4-amidinophenyl)furan], is the active metabolite of this drug. The objective of this study was to determine the mechanism of action of DB75 in Plasmo...
3-D compilation of z-series images show DB75 localization is distinct from food vacuole. 3-D localization of DB75 (blue) is distinct from red LysoTracker (food vacuole) in P. falciparum trophozoite. Video may be viewed with Windows Media Player.
3-D compilation of z-series images show DB75 localization is distinct from mitochondria. 3-D co-localization of DB75 with Draq5™ (aqua color) is distinct from red mitotracker (mitochondria) in P. falciparum schizont. Video may be viewed with Windows Media Player.
Developmentally expressed genes assessed for changes with DB75 exposure. Primers and stage specificity of 6 gene transcripts.
Diamidine 1 (pentamidine) and 65 analogues (2-66) have been tested for in vitro antiprotozoal activities against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani, and for cytotoxicity against mammalian cells. Dications 32, 64, and 66 exhibited antitrypanosomal potencies equal or greater than melarsoprol (IC(50) = 4 nM)...
A series of 37 dicationically substituted bis(phenoxymethyl)benzene bis(phenoxymethyl)naphthalene, and bis(benzyloxy)naphthalene analogues of pentamidine was prepared and evaluated for antiprotozoal activities and cytotoxicity in in vitro. 1,3-Bis(4-amidinophenoxymethyl)benzene (1) was the most active against Trypanosoma brucei rhodesiense (IC(50)=...
Most A/T specific heterocyclic diamidine derivatives need at least four A/T base pairs for tight binding to the DNA minor groove. Addition of a GC base pair to A/T sequences typically causes a large decrease in binding constant. The ability to target biologically important sequences of DNA could be significantly increased if compounds that could re...
Owing to the lack of oral drugs for human African trypanosomiasis, patients have to be hospitalized for 10 to 30 days to facilitate
treatment with parenterally administered medicines. The efficacy of a novel orally administered prodrug, 2,5-bis(4-amidinophenyl)-furan-bis-O-methlylamidoxime (pafuramidine, DB289), was tested in the vervet monkey (Chl...
African sleeping sickness is a fatal parasitic disease, and all drugs currently in use for treatment have strong liabilities.
It is essential to find new, effective, and less toxic drugs, ideally with oral application, to control the disease. In this
study, the aromatic diamidine DB75 (furamidine) and two aza analogs, DB820 and DB829 (CPD-0801), as...
A series of cationically substituted 2-phenylbenzofurans 1- 49 have been synthesized, and their in vitro antiprotozoal properties against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani, as well as cytotoxicity against mammalian cells, have been evaluated. Eight dications exhibited antitrypanosomal activities comparab...
Cases of visceral leishmaniasis, one of the most neglected tropical diseases, are increasing globally. Dogs are considered an important reservoir host for visceral leishmaniasis in people. The first cases of human visceral leishmaniasis in Vietnam have recently been reported. Blood samples were collected from 41 dogs in rural Vietnam. Sera were exa...
The human cytochrome P450 (P450) superfamily consists of membrane-bound proteins that metabolize a myriad of xenobiotics and endogenous compounds. Quantification of P450 expression in various tissues under normal and induced conditions has an important role in drug safety and efficacy. Conventional immunoquantification methods have poor dynamic ran...
The antiparasitic activity of aromatic diamidine drugs, pentamidine and furamidine, depends on their entry into the pathogenic protozoa via membrane transporters. However, no such diamidine transporter has been identified in mammalian cells. The goal of this study is to investigate whether these dicationic drugs are substrates for human organic cat...
The choice of drugs for the treatment of sleeping sickness is extremely limited. To redress this situation, the recently synthesised diamidine, 2,5-bis(4-amidinophenyl)-furan (DB75, furamidine) and its methamidoxime prodrug, 2,5-bis(4-amidinophenyl)-furan-bis-O-methylamidoxime (DB289, pafuramidine) were, together with pentamidine, evaluated for eff...
Old World cutaneous leishmaniasis is caused by infection with Leishmania major and Leishmania tropica. Pentamidine and related dications exhibit broad spectrum antiprotozoal activity. Based on the previously reported efficacy of these compounds against related organisms, 18 structural analogs of pentamidine were evaluated for in vitro antileishmani...
The synthesis and evaluation of 2,5-bis[4-(N-ethoxycarbonyl-N'-isopropyl)amidinophenyl]furan, 2,5-bis[4-(N-2,2,2-trichloroethoxycarbonyl-N'-isopropyl)amidinophenyl]furan and 2,5-bis[4-(N-cyclopentyl-N'-2,2,2-trichloroethoxycarbonyl)amidinophenyl]furan as prodrugs of bis-N-alkylamidines are reported. The results show that the bis-2,2,2-trichloroethy...
This review discusses the challenges of chemotherapy for human African trypanosomiasis (HAT). The few drugs registered for use against the disease are unsatisfactory for a number of reasons. HAT has two stages. In stage 1 the parasites proliferate in the haemolymphatic system. In stage 2 they invade the central nervous system and brain provoking pr...
Human African trypanosomiasis (HAT) is a fatal tropical disease caused by infection with protozoans of the species Trypanosoma brucei gambiense and T. b. rhodesiense. An oral prodrug, DB289, is a promising new therapy undergoing phase III clinical trials for early-stage HAT. DB289 is metabolically
converted to the active trypanocidal diamidine DB75...
Pafuramidine is a novel orally active antimalarial. To identify a combination partner, we measured the in vitro antimalarial activities of the active metabolite, DB75, with amodiaquine, artemisinin, atovaquone, azithromycin, chloroquine, clindamycin, mefloquine, piperaquine, pyronaridine, tafenoquine, and tetracycline. None of the drugs tested demo...
Forty three cationic bisbenzofurans were synthesized either by interaction of o-hydroxyaldehydes with alpha-halogenated ketones followed by intramolecular ring closure or by a copper- or palladium-mediated heteroannulation of substituted o-iodophenols with terminal acetylenes. In vitro antiprotozoal activities of compounds 1-43 against Trypanosoma...
Leishmania infantum and Trypanosoma cruzi are zoonotic parasites that are endemic throughout many parts of Latin America. Infected dogs play an important role in transmission of both parasites to humans. A serological survey of Leishmania and Trypanosoma infection was conducted on 365 dogs from São Paulo, Brazil and Bogatá, Colombia, South America....
CYP4F enzymes, including CYP4F2 and CYP4F3B, were recently shown to be the major enzymes catalyzing the initial oxidative O-demethylation of the antiparasitic prodrug pafuramidine (DB289) by human liver microsomes. As suggested by a low oral bioavailability, DB289 could undergo first-pass biotransformation in the intestine, as well as in the liver....
Wild canids are reservoir hosts for Leishmania infantum and Trypanosoma cruzi. The present study examined the prevalence of antibodies to these zoonotic parasites in a population of wild canids from a nonagricultural setting in South Carolina. Sera from 26 gray foxes (Urocyon cinereoargenteus) and 2 coyotes (Canis latrans) were examined for antibod...
RT29 is a dicationic diamidine derivative that does not obey the classical "rules" for shape and functional group placement that are expected to result in strong binding and specific recognition of the DNA minor groove. The compound contains a benzimidazole diphenyl ether core that is flanked by the amidine cations. The diphenyl ether is highly twi...
3,5-bis(4-amidinophenyl)isoxazole (3)-an analogue of 2,5-bis(4-amidinophenyl)furan (furamidine) in which the central furan ring is replaced by isoxazole-and 42 novel analogues were prepared by two general synthetic pathways. The 43 isoxazole derivatives were assayed against Trypanosoma brucei rhodesiense (T. brucei rhodesiense) STIB900, Plasmodium...
Canine leishmaniasis caused by Leishmania infantum is enzootic in the North American foxhound population. Currently available chemotherapy for canine leishmaniasis is not completely effective and relapses are common in treated dogs. Pentamidine and related aromatic diamidines possess broad spectrum antiprotozoal activity. The in vitro antileishmani...
Seven analogs of pentamidine were tested for their activity against an immunosuppressed rat model of Pneumocystis carinii pneumonia. Structural alterations of the pentamidine molecule included variations of the alkyl chain linking the two p-amidino phenoxy moieties and relocation of the amidine groups from the para to the meta position on the pheno...
DB289 [2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime] is biotransformed to the potent antiparasitic diamidine DB75 [2,5-bis(4-amidinophenyl) furan] by sequential oxidative O-demethylation and reductive N-dehydroxylation reactions. Previous work demonstrated that the N-dehydroxylation reactions are catalyzed by cytochrome b5/NADH-cytochrome b5...
Human African trypanosomiasis is a devastating disease with only a few treatment options, including pentamidine. Diamidine compounds such as pentamidine, DB75, and DB820 are potent antitrypanosomal compounds. Previous investigations have shown that diamidines accumulate to high concentrations in trypanosomes. However, the mechanism of action of thi...
A novel trypanocide, 2,5-bis(4-amidinophenyl)furan (DB75), in its prodrug amidoxime-derivative form, 2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime (DB289), is in trials as the first orally administered drug for human African trypanosomiasis. DB75 is a diamidine. Resistance to some diamidines correlates to loss of uptake via the P2 aminopurine...
Purpose: DB1227 is the methamidoxime prodrug of the aromatic diamidine DB1210, a new candidate drug to treat malaria. Our objective is to evaluate the pharmacokinetics of DB1227 and DB1210 after single oral doses in Aotus monkey, which is used as a primate model of malaria.
Method: DB1227 was administered orally to Aotus monkeys as single doses of...
Citations
... Furthermore, different isolates of veterinary trypanosomes have shown great variability in their drug sensitivity profile, which often leads to treatment failure and devastating impact on agricultural and rural economy of developing countries [11,16]. However, with the genetic differences between the three species causing AAT becoming clearer, it appears that differences in drug sensitivity can result from differences in their capacity to internalize the drugs [17,18] and loss of the unique transporters involved often contributes to drug resistance [19][20][21][22]. It is thus clear that in AAT drug design, one should consider exploiting the specific transporters for guiding drugs to their intracellular targets. ...
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... revealed that TbAQP1 and TbAQP3 encode canonical selectivity filters, whereas TbAQP2 possesses a unique selectivity filter 15 . Previous studies have indicated that TbAQP2 transports pentamidine and melarsoprol via direct permeation 16,19,20 . However, melarsoprol and pentamidine exhibit significant structural differences compared to typical AQP substrates. ...
... This includes information on target transcriptional responses associated with diseases and/or drug therapies, public gene expression data, target-disease associations, sequence and structural homology, and identity between targets [111,116]. As an example, Santos and colleagues employed target fishing and molecular docking tools to discover the target of a known active molecule against T. cruzi from a pool of 30 possible targets, showing that the molecule interacts directly with DNA, resulting in the parasite malformation [117]. ...
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... The main role of the inward rectifier K + current (I K1 ) is to regulate intracellular potassium concentration, maintain intracellular and extracellular electrochemical balance. The inhibition of I K1 , a major determinant of the final repolarization phase, results in prolonged repolarization and shortened post-repolarization refractory period, but has no significant effect on the total duration of AP [53]. A translational study conducted in 2022 demonstrated that methadone, a potent inhibitor of I K1 , can lead to an increase in U waves on surface ECGs [16] (Fig. 1). ...
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... were prepared via methylation on the treatment of their corresponding diamidoximes 208a,b with (CH 3 ) 2 SO 4 . The diamidine derivatives 210a,b were prepared by treatment of dinitrile derivatives 207a,b with LiN(TMS) 2 , followed by de-protection of the silylated amidines with ethanolic HCl to furnish the corresponding diamidines (Scheme 59) [115]. ...
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... During our research, we focused on the discovery of novel aza heterocyclic compounds that can be useful in antiprotozoal chemotherapy [12][13][14][15][16][17][18][19][20]; we have formerly developed various series of 2,9-bis[(substituted-aminomethyl)phenyl]phenanthrolines (series A-B), 2,4-bis[(substituted-aminomethyl)phenyl]quinolines, 1,3-bis[(substituted-aminomethyl) phenyl]isoquinoline and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives (series C) designed as antiprotozoal candidates, which could bind to Plasmodium falciparum DNA G-quadruplexes [17][18][19][20] in order to bypass the resistance mechanisms deployed by the parasites and also based on efflux. Indeed, it has previously been described that the telomeres of various protozoa could constitute attractive drug targets [21][22][23][24], and telomerase activity is observed in gametocytes and during the transition to the erythrocytic stage of the parasite P. falciparum [25]. The telomeric 3' G-overhang area of P. falciparum is a repetition of degenerate unit 5 GGGTTYA3 (where Y could be T or C) [26], which can fold into intramolecular G-quadruplex [27]. ...
... The dinitrile compound 102 (R = H) was prepared by adopting Suzuki coupling reaction between bromo derivative 70 and 4-cyanophenylboronic acid [9]. The preparation of substituted nicotinamidine 104 (R = CH 3 ) was reported from the corresponding dinitrile 102 (R = CH 3 ) which was made from nicotinonitrile derivative 101 adopting Heck coupling conditions [87]. Deuterium-labelled nicotinamidine derivative 104-d4 (1,4-disubstituted phenyl ring = -C 6 D 4 -) was prepared on the treatment of compound 101 with 4-bromobenzonitrile-d4 adopting Heck coupling reaction using Pd(PPh 3 ) 4 as a catalyst and KOAc as a base (Scheme 33) [88]. ...
... This compound was a potent inhibitor of the growth of extracellular forms of L. donovani and T. cruzi in vitro, but failed against intramacrophage infections [170,174]. More recently, other novel diamidines have been assayed against the agents of animal trypanosomiasis T. congolense and T. vivax, showing curative outputs in murine models [175]. ...
... Such conformational effects can be exploited to control the conformations of amino acid side chains, and this has been demonstrated most notably for proline [27, [210][211][212][213][214][215][216]. For example, fluorination at the 4-position of the proline side chain (i.e., 33 and 66, Figure 7) can stabilize either the C 4 -endo or C 4 -exo pucker depending on the configuration of the fluorinated stereocentre, which is attributable to σ CH →σ* CF hyperconjugation in each case. ...
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... cruzi IC50 20 nM and T. b. brucei IC50 24 nM). The most potent agent could also be well tolerated in several [66] devised similar derivatives (35-38) (Fig. 13) and deduced that fluorination of the phenyl ring could potentiate the antitrypanosomal activity. In this regard, derivatives 35-38 exhibited IC50 values of 9, 12, 9.9, and 9.7 nM against T. b. rhodesiense, respectively. ...
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