Hit-to-lead optimization of novel phenyl imidazole carboxamides that are active against Leishmania donovani

  • Eur J Med Chem. 2022 Oct 5:240:114577. doi: 10.1016/j.ejmech.2022.114577.
Nicole McNamara  1 ,  Eleanor Saunders  2 ,  Swapna Varghese  1 ,  Rebecca Zheng  1 ,  Kaylene Simpson  3 ,  Devika M Varma  4 ,  Monica M Johnson  4 ,  M Shamim Hasan Zahid  4 ,  Eric M Bachelder  4 ,  Kristy M Ainslie  4 ,  Joo Hwan No  5 ,  Dahae Koh  6 ,  David Shum  6 ,  Nirmal Das  7 ,  Binita Patra  7 ,  Jayasree Roy  8 ,  Arindam Talukdar  7 ,  Dipyman Ganguly  8 ,  Malcolm McConville  2 ,  Jonathan Baell  9
Affiliations
  • 1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia.
  • 2. Department of Biochemistry and Pharmacology, Bio21 Institute of Molecular Science and Biotechnology (Bio21), University of Melbourne, Parkville, Victoria, 3052, Australia.
  • 3. Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centr, Victorian Comprehensive Cancer Centre, 305 Grattan St, Melbourne, Victoria, 3000, Australia.
  • 4. Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 5. Institut Pasteur Korea, Leishmania Research Laboratory, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, Republic of Korea.
  • 6. Institut Pasteur Korea, Screening Discovery Platform, 16, Daewangpangyo-ro 712 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, Republic of Korea.
  • 7. Department of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata, 700032, West Bengal, India.
  • 8. IICB-Translational Research Unit of Excellence, Department of Cancer Biology and Inflammatory Disorders, CSIR-Indian Institute of Chemical Biology, CN6, Sector V, Salt Lake, Kolkata, 700091, West Bengal, India.
  • 9. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia; School of Pharmaceutical Sciences, Nanjing Tech University, No. 30 South Puzhu Road, Nanjing, 211816, People's Republic of China; Australian Translational Medicinal Chemistry Facility (ATMCF), Monash University, Parkville, Victoria, 3052, Australia. Electronic address: [email protected].
PMID: 35810535 DOI: 10.1016/j.ejmech.2022.114577
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 of compounds maintained low cytotoxicity against human THP-1 macrophages that are target cells for these pathogens. New lead compounds identified within this study also maintained desirable physicochemical properties, improved metabolic stability in vitro and displayed no significant mitotoxicity against HepG2 cell lines. This compound class warrants continued investigation towards development as a novel treatment for Visceral Leishmaniasis.

Keywords
Early hit-to-lead SAR exploration; L. donovani inhibitors; Neglected tropical disease; Phenyl imidazole carboxamides; Visceral leishmaniasis.