Issue 12, 2011

Design, synthesis and biological evaluation of novel benzothiazole and triazole analogs as falcipain inhibitors

Abstract

We describe the design, combinatorial library synthesis and biological evaluation of compounds with benzothiazole and triazole cores as inhibitors of falcipain, cysteine proteases of the malaria parasite Plasmodium falciparum. These classes were originally discovered by structure-based virtual screening of a focused cysteine protease inhibitor library. Fifteen structural analogs of both series showed moderate inhibition of falcipain-2. Two compounds, 41 and 42, were predicted by docking studies to interact with polar residues buried in the S2 pockets of falcipain-2 and -3, and these compounds inhibited both enzymes. Compound 41 also demonstrated activity against chloroquine-resistant cultured P. falciparum parasites at the lower micromolar concentration. Evaluation of 41 and 42 against mammalian cysteine proteases of papain family suggest these polar residues of the S2 pocket may not be important for the design of selective inhibitors against falcipain.

Graphical abstract: Design, synthesis and biological evaluation of novel benzothiazole and triazole analogs as falcipain inhibitors

Supplementary files

Article information

Article type
Concise Article
Submitted
18 May 2011
Accepted
09 Sep 2011
First published
27 Sep 2011

Med. Chem. Commun., 2011,2, 1201-1207

Design, synthesis and biological evaluation of novel benzothiazole and triazole analogs as falcipain inhibitors

F. Shah, Y. Wu, J. Gut, Y. Pedduri, J. Legac, P. J. Rosenthal and M. A. Avery, Med. Chem. Commun., 2011, 2, 1201 DOI: 10.1039/C1MD00129A

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