New heteroaryl carbamates: Synthesis and biological screening in vitro and in mammalian cells of wild-type and mutant HIV-protease inhibitors |
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Authors: | Francesco Tramutola Maria Francesca Armentano Federico Berti Lucia Chiummiento Paolo Lupattelli Rosarita DOrsi Rocchina Miglionico Luigi Milella Faustino Bisaccia Maria Funicello |
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Institution: | 1. Dipartimento di Scienze, Università della Basilicata, Via Ateneo Lucano 10, 85100 Potenza, Italy;2. Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Trieste, via Giorgieri, 1, 34127 Trieste, Italy |
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Abstract: | New heteroaryl HIV-protease inhibitors bearing a carbamoyl spacer were synthesized in few steps and high yield, from commercially available homochiral epoxides. Different substitution patterns were introduced onto a given isopropanoyl-sulfonamide core that can have either H or benzyl group. The in vitro inhibition activity against recombinant protease showed a general beneficial effect of both carbamoyl moiety and the benzyl group, ranging the IC50 values between 11 and 0.6?nM. In particular, benzofuryl and indolyl derivatives showed IC50 values among the best for such structurally simple inhibitors. Docking analysis allowed to identify the favorable situation of such derivatives in terms of number of interactions in the active site, supporting the experimental results.The inhibition activity was also confirmed in HEK293 mammalian cells and was maintained against protease mutants. Furthermore, the metabolic stability was comparable with that of the commercially available inhibitors. |
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Keywords: | HIV-protease inhibitors Heteroaryl carbamates Drug-resistance Synthesis biological screening Modeling |
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