New heteroaryl carbamates: Synthesis and biological screening in vitro and in mammalian cells of wild-type and mutant HIV-protease inhibitors

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 IC 50 values between 11 and 0.6 nM. In particular, benzofuryl and indolyl derivatives showed IC 50 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.

The Pseudo-Symmetric N-benzyl Hydroxyethylamine Core in a New Series of Heteroarylcarboxyamide HIV-1 Pr Inhibitors: Synthesis, Molecular Modeling and Biological Evaluation

“…As HIV protease has been shown to exist as a C2-symmetric homodimer in its active form, several dipeptide isosteres, such as diaminoalcohol, diaminodiol and hydroxyethylhydrazine, have also been employed in the development of pseudo-symmetric inhibitors (that is, inhibitors that are lacking the same C2 symmetry of the enzyme, but bear the same group at P1 and P1') [24] (Figure 2). Recently the preparation and the activity, in vitro and in mammalian cells, of new HIV protease inhibitors, compounds 1 and 2, were reported by our group (Figure 1) [22,23].…”

“…The general structure of these newly synthesized compounds is reported as A in Figure 2. The structure takes into account the outcomes of our previous evaluations and the indications obtained in the models developed and described in refs [13,14,[16][17][18]22,23]. In order to obtain a pseudo-symmetric hydroxyethylamine core, the isobutyl portion present in the structure of compounds 1 and 2 (Figure 1) was replaced with a benzyl group.…”

“…Recently the preparation and the activity, in vitro and in mammalian cells, of new HIV protease inhibitors, compounds 1 and 2, were reported by our group ( Figure 1 ) [ 22 , 23 ].…”

“…They were designed having heterocycle as the P2 ligand linked by a carboxyamidic or carbammic moiety to the core, with or without the benzyl group, and a 3,4-dimethoxyphenylsulfonyl- N -isobutylamide [ 22 ] or a 4-methoxyphenylsulfonyl- N -isobutylamide [ 23 ] as the P2’ ligand. Compounds with benzyl in the core showed in vitro activity against native protease with IC 50 values in the range of <0.6–13 nM.…”

“…The general structure of these newly synthesized compounds is reported as A in Figure 2 . The structure takes into account the outcomes of our previous evaluations and the indications obtained in the models developed and described in refs [ 13 , 14 , 16 , 17 , 18 , 22 , 23 ].…”