Synthesis and pharmacological evaluation of mono-arylimidamides as antileishmanial agents

Zhu, Xiaohua; Farahat, Abdelbasset A.; Mattamana, Meena; Joice, April C.; Pandharkar, Trupti; Holt, Elizabeth; Banerjee, Mohua; Gragg, Jamie L.; Hu, Linping; Kumar, Arvind; Yang, Sihyung; Wang, Michael Zhuo; Boykin, David W.; Werbovetz, Karl A.

doi:10.1016/j.bmcl.2016.03.082

Cited by 16 publications

(13 citation statements)

References 25 publications

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“…Synthesis of the indole-bichalcophene diamidine derivatives 4a-d is outlined in Scheme 1 . The bis-nitriles 3a-d were prepared by Stille coupling [11] , [12] , [13] reaction between the bromo derivatives 1a-d and 2-(trimethylstannyl)-1-( tert -butoxycarbonyl)- 1 H -indole-6-carbonitrile 2 using palladium tetrakistriphenylphosphine as a catalyst. The bis-nitriles 3a-d on reaction with a THF solution of lithium bis(trimethylsilyl)amide [14] , followed by treatment with ethanolic HCl yielded the hydrochloride salts of the diamidines 4a-d .…”

Section: Resultsmentioning

confidence: 99%

Indole and Benzimidazole Bichalcophenes: Synthesis, DNA Binding and Antiparasitic Activity

Farahat

Ismail

Kumar

et al. 2018

European Journal of Medicinal Chemistry

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A novel series of indole and benzimidazole bichalcophene diamidine derivatives were prepared to study their antimicrobial activity against the tropical parasites causing African sleeping sickness and malaria. The dicyanoindoles needed to synthesize the target diamidines were obtained through Stille coupling reactions while the bis-cyanobenzimidazoles intermediates were made via condensation/cyclization reactions of different aldehydes with 4-cyano-1,2-diaminobenzene. Different amidine synthesis methodologies namely, lithium bis-trimethylsilylamide (LiN[Si(CH3)3]2) and Pinner methods were used to prepare the diamidines. Both types (indole and benzimidazole) derivatives of the new diamidines bind strongly with the DNA minor groove and generally show excellent in vitro antitrypanosomal activity. The diamidino-indole derivatives also showed excellent in vitro antimalarial activity while their benzimidazole counterparts were generally less active. Compound 7c was highly active in vivo and cured all mice infected with Trypanosoma brucei rhodesiense, a model that mimics the acute stage of African sleeping sickness, at a low dose of 4 × 5 mg/kg i.p. and hence 7c is more potent in vivo than pentamidine.

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Section: Resultsmentioning

confidence: 99%

Indole and Benzimidazole Bichalcophenes: Synthesis, DNA Binding and Antiparasitic Activity

Farahat

Ismail

Kumar

et al. 2018

European Journal of Medicinal Chemistry

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“…In another study by Zhu et al (2016), 18 compounds containing a single terminal group of pyridylimidamide (mono‐AIAs) were synthetized and evaluated for their antileishmanial potential in relation to standard drugs. Only three compounds showed good efficacy and low toxicity, in which Compound 1b had IC 50 of 310 nM, Compound 1k with IC 50 140 nM and Compound 1d with IC 50 340 nM, compared to AmB with IC 50 40 nM.…”

Section: Resultsmentioning

confidence: 99%

Recent strategies for the development of oral medicines for the treatment of visceral leishmaniasis

Souza

Costa

Silva

et al. 2020

Drug Development Research

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Considered prevalent in many countries on five continents, especially in low‐income regions, leishmaniasis is a neglected tropical disease classified by World Health Organization as one of the diseases for which the development of new treatments is a priority. It is an infectious disease caused by protozoa of the genus Leishmania, whose species may cause different clinical manifestations, such as cutaneous and visceral leishmaniasis (VL). Treatment is exclusively by drug therapy, as it has not been possible to develop vaccines yet. Currently available drugs are not fully effective in all cases; they have parenteral administration and exhibit a number of serious and very common adverse effects. The only oral drug available is expensive and it is not available in many endemic countries. Injectable administration is the main problem of treatments, since it requires patients to go to health centers, hospitalization and professional administration, which are conditions that are not adapted to the reality of the poverty conditions of patients with the disease. In this context, the development of an oral medicine has become a focus as it may solve many of these issues. Based on this scenario, this review aimed to investigate which therapeutic alternatives have been studied for the development of oral drugs directed to the treatment of human VL.

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“…Among a series of carboline derivatives reported by Manda et al [98], compounds 25a (IC 50 = 12.7 µM) and 25b (IC 50 = 9.1 µM), which are derivatives of the commercially available tetrahydro-β-carboline prepared in a single procedure were the best candidates against L. donovani (promastigotes). Zhu et al [99] reported compounds 26a and 26b , which are derived from arylamidamide using the reaction between amino diarylfurans and 2-pyridyl thioimidate analogs, as the most active antileishmanial agents against both intracellular L. donovani and L. amazonensis amastigotes, with IC 50 values ranging from 0.13 to 0.31 µM. A series of 4-alkapolyenylpyrrolo[1,2-a]quinoxaline derivatives, including compounds 27a and 27b , which exhibited remarkable inhibitory potential against two Leishmania spp.…”

Section: Recent Progress Of Antiprotozoan Agentsmentioning

confidence: 99%

Recent Advances in the Discovery of Novel Antiprotozoal Agents

et al. 2019

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Parasitic diseases have serious health, social, and economic impacts, especially in the tropical regions of the world. Diseases caused by protozoan parasites are responsible for considerable mortality and morbidity, affecting more than 500 million people worldwide. Globally, the burden of protozoan diseases is increasing and is been exacerbated because of a lack of effective medication due to the drug resistance and toxicity of current antiprotozoal agents. These limitations have prompted many researchers to search for new drugs against protozoan parasites. In this review, we have compiled the latest information (2012–2017) on the structures and pharmacological activities of newly developed organic compounds against five major protozoan diseases, giardiasis, leishmaniasis, malaria, trichomoniasis, and trypanosomiasis, with the aim of showing recent advances in the discovery of new antiprotozoal drugs.

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Synthesis and pharmacological evaluation of mono-arylimidamides as antileishmanial agents

Abstract: Graphical abstract

Cited by 16 publications

References 25 publications

Indole and Benzimidazole Bichalcophenes: Synthesis, DNA Binding and Antiparasitic Activity

Indole and Benzimidazole Bichalcophenes: Synthesis, DNA Binding and Antiparasitic Activity

Recent strategies for the development of oral medicines for the treatment of visceral leishmaniasis

Recent Advances in the Discovery of Novel Antiprotozoal Agents

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