Hit-to-lead optimization of a benzene sulfonamide series for potential antileishmanial agents
Paul J Koovits1, Marco A Dessoy1, An Matheeussen2
1Institute of Chemistry, University of Campinas (UNICAMP) Rua Josué de Castro, S/N, Cidade Universitária Campinas SP 13083-861 Brazil ldias@iqm.unicamp.br +55 19 3521 3097.
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.
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