Journal article
Hit-to-lead optimization of novel phenyl imidazole carboxamides that are active against Leishmania donovani
N McNamara, E Saunders, S Varghese, R Zheng, K Simpson, DM Varma, MM Johnson, MS Hasan Zahid, EM Bachelder, KM Ainslie, JH No, D Koh, D Shum, N Das, B Patra, J Roy, A Talukdar, D Ganguly, M McConville, J Baell
European Journal of Medicinal Chemistry | Published : 2022
Abstract
Visceral leishmaniasis is a potentially fatal disease caused by the parasitic protists, Leishmania donovani and L. infantum. Current treatments remain unsuitable due to cost, the need for hospitalization, variable efficacy against different species, toxicity and emerging resistance. Herein, we report the SAR exploration of the novel hit 4-Fluoro-N-(5-(4-methoxyphenyl)-1-methyl-1H-imidazole-2-yl)benzamide [1] previously identified from a high throughput screen against Trypanosoma brucei, Trypanosoma cruzi and Leishmania donovani. An extensive and informative set of analogues were synthesized incorporating key modifications around the scaffold resulting in improved potency, whilst the majority..
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Funding Acknowledgements
Funding was provided by the Australian Government through an Australian Government Research Training Program (RTP) Scholarship to NM, the Australia -India Strategic Research Fund (AISRF) and National Health and Medical Research Council (NHMRC) Principal Research Fellowships to JB and MJM. The authors thank Glax- oSmithKline, Tres Cantos, Spain for allowing for us to investigate hit compounds taken from their HTS. The Centre for Drug Candidate Optimization (CDCO) of the Monash Institute of Pharmaceutical Sciences (MIPS) tested the physicochemical parameters and in vitro metabolic stability of the lead compounds listed in Tables 8 and 9 The Australian Translational Medicinal Chemistry Facility (ATMCF) within Monash Institute of Pharmaceutical Sciences (MIPS) , acknowledges the support of the Australian Government's National Collaborative Research Infrastructure Strategy (NCRIS) program via Therapeutic Innovation Australia (TIA) .