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


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]



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.


1   Institute of Chemistry, University of Campinas (UNICAMP), Rua Josué de Castro, S/N, Cidade Universitária, Campinas, SP, Brazil

2   Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium

3   Laboratory of Medicinal and Computational Chemistry, Physics Institute of Sao Carlos, University of Sao Paulo, Av. Joao Dagnone 1100, Sao Carlos-SP, Brazil

4   Drugs for Neglected Diseases initiative (DNDi), 15 Chemin Louis-Dunant, 1202 Geneva, Switzerland


Link to article:   https://pubs.rsc.org/en/content/articlelanding/2020/MD/D0MD00165A#!divAbstract