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

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.

SUBMITTER: Koovits PJ

PROVIDER: S-EPMC8126888 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Koovits Paul J PJ Dessoy Marco A MA Matheeussen An A Maes Louis L Caljon Guy G Ferreira Leonardo L G LLG Chelucci Rafael C RC Michelan-Duarte Simone S Andricopulo Adriano D AD Campbell Simon S Kratz Jadel M JM Mowbray Charles E CE Dias Luiz C LC

RSC medicinal chemistry 20200825 11

A series of benzene sulphonamides with good potency and selectivity against <i>Leishmania</i> 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 likel ...[more]

PMID: 34085041

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