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.

Computational Methods in Drug Discovery

“…They separated the center of mass movement of ligand from its internal and rotational motions. (Friedman and Caflisch, 2009), target for malaria Flavivirus Proteases (Ekonomiuk et al, 2009a,b), target for WNV and Dengue virus Tyrosine kinase erythropoietin-producing human hepatocellular carcinoma receptor B4 (EphB4) (Lafleur et al, 2009) FlexX Plasmepsin II and IV inhibitors (Luksch et al, 2008), malaria Anthrax edema factor Pneumococcal peptidoglycan deacetylase inhibitors (Bui et al, 2011) Glide Aurora kinases inhibitors (Warner et al, 2006) Falcipain inhibitors (Shah et al, 2011) Cytochrome P450 inhibitors (Caporuscioi et al, 2011) Surflex Topoisomerase I, anticancer (optimization) DOCK FK506 immunophilin (Zhao et al, 2006) BCL6, oncogene in B-cell lymphomas (Cerchietti et al, 2010) 348…”

A comprehensive review in current developments of benzothiazole-based molecules in medicinal chemistry

“…Non-peptidic active analogs of the BTA and triazole series synthesized and are evaluated for inhibitors of falcipain, cysteine proteases of the malaria parasite P. falciparum. Compounds (231,232), with protonated amines inhibited both hemoglobinases (FP-2 and, FP-3) and these two compounds also displayed activity against homologous mammalian cysteine proteases lacking corresponding polar residues, suggesting less significance of these residues in the design of selective inhibitors against FPs [268]. The structures for BTA as antimalarial agents are shown in Fig.…”

Quinoline-triazole hybrids inhibit falcipain-2 and arrest the development ofPlasmodium falciparumat the trophozoite stage

“…31 Fluconazole, voriconazole and itraconazole are some of the important triazole core moiety-based drugs. Recently, admirable triazole- based FP2 inhibitors have been developed [32][33][34] among which a few are given in (Fig. 2).…”