Hit-to-lead optimization of a benzene sulfonamide series for potential antileishmanial agents

Author(s):Show less -

Koovits, Paul J. ^[1] ; Dessoy, Marco A. ^[1] ; Matheeussen, An ^[2] ; Maes, Louis ^[2] ; Caljon, Guy ^[2] ; Ferreira, Leonardo L. G. ^[3] ; Chelucci, Rafael C. ^[3] ; Michelan-Duarte, Simone ^[3] ; Andricopulo, Adriano D. ^[3] ; Campbell, Simon ^[4] ; Kratz, Jadel M. ^[4] ; Mowbray, Charles E. ^[4] ; Dias, Luiz C. ^[1]

Affiliation

^[1] Univ Estadual Campinas, UNICAMP, Inst Chem, Rua Josue de Castro S-N, Cidade Univ, BR-13083861 Campinas, SP - Brazil

^[2] Univ Antwerp, Lab Microbiol Parasitol & Hyg LMPH, Univ Pl 1, B-2610 Antwerp - Belgium

^[3] Univ Sao Paulo, Phys Inst Sao Carlos, Lab Med & Computat Chem, Av Joao Dagnone 1100, BR-13563120 Sao Carlos, SP - Brazil

^[4] Drugs Neglected Dis Initiat DNDi, 15 Chemin Louis Dunant, CH-1202 Geneva - Switzerland

• Document type: Journal article
• Source: RSC MEDICINAL CHEMISTRY; v. 11, n. 11, p. 1267-1274, NOV 1 2020.
• Web of Science Citations: 0

Abstract

A series of benzene sulphonamides with good potency and selectivity against Leishmania spp. intracellular amastigotes was identified by high-throughput screening. Approximately 200 compounds were synthesized as part of a hit-to-lead optimization program. The potency of the series appears to be strongly dependent on lipophilicity, making the identification of suitable orally available candidates challenging due to poor pharmacokinetics. Despite not identifying a clinical candidate, a likely solvent exposed area was found, best exemplified in compound 29. Ongoing detailed mode-of-action studies may provide an opportunity to use target-based medicinal chemistry to overcome the issues with the current series. (AU)

• FAPESP's process: 15/19495-5 - Compounds synthesis for the treatment of Chagas Disease at RIDCs/FAPESP/DNDi
• Grantee: Paul John Koovits
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 15/50655-9 - FAPESP/MMV/DNDi/UNICAMP/USP Consortium to discover new drugs for the treatment of tropical parasitic diseases
• Grantee: Luiz Carlos Dias
• Support type: Research Grants - Research Partnership for Technological Innovation - PITE