Synthesis and anti-HIV activity evaluation of 2-(4-(naphthalen-2-yl)-1,2,3-thiadiazol-5-ylthio)-N-acetamides as novel non-nucleoside HIV-1 reverse transcriptase inhibitors

Abstract

A series of 2-(4-(naphthalen-2-yl)-1,2,3-thiadiazol-5-ylthio)acetamide (TTA) derivatives were synthesized and evaluated as potent inhibitors of HIV-1. Among the newly disclosed TTAs, compounds 7f, 7g and 7c were the most potent inhibitors of HIV-1 replication of the series (EC₅₀ = 0.17 ± 0.02, 0.36 ± 0.19 and 0.39 ± 0.05 μM, respectively), coupled with a reasonable selectivity index (SI > 1452, >845, and >774, respectively). They possess improved or similar HIV-1 inhibitory activity compared with NVP (EC₅₀ = 0.208 μM) and DLV (EC₅₀ = 0.320 μM). The preliminary structure–activity relationships among the newly synthesized congeners are discussed briefly and rationalized by docking studies.

Introduction

The reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1) is a key target for inhibition of HIV-1 replication. The RT can be inhibited by two classes of drug belonging either to the nucleoside reverse transcriptase inhibitors (NRTIs) or to the non-nucleoside reverse transcriptase inhibitors (NNRTIs). NNRTIs have proved to be an important component of cocktail therapy [1], [2], [3], [4]. However, the long-term usage of NNRTIs in HIV/AIDS patients may eventually lead to the development of virus-drug resistance. Therefore, it is imperative to look for novel NNRTIs with potent and broad spectrum anti-HIV mutant activity that are also safe and have excellent pharmacokinetic profiles [5].

Among the representatives of the NNRTIs, sulfanyltriazoles (I) and sulfanyltetrazoles (II) (Fig. 1) have interesting structures and offer various opportunities on the skeleton of sulfanylazoles as lead compounds [6], [7], [8], [9], [10], [11]. Initially, we developed a series of 2-(4-(2,4-dichlorophenyl)-1,2,3-thiadiazol-5-ylthio)-N-acetamide (TTA) analogues (III, Fig. 1), which exhibited significant anti-HIV-1 activities [12], [13]. Inspired by these promising results and in continuation of our work on the search of novel NNRTIs [14], [15], we thought it worthwhile to synthesize new compounds of TTAs having 4-(2-naphthoyl) moiety attached to 1,2,3-thiadiazole, with the aim to strengthen the π–π stacking interaction between the inhibitors and aromatic residues (such as Tyr188 or Tyr181) of RT and to obtain new biologically active compounds (Fig. 2).

Molecular modeling studies of the sulfanyltriazole/tetrazoles family [6], [10], [11], [13] revealed that the N-substituted anilide phenyl ring extends from the NNRTI binding pocket to the protein/solvent interface, which presents an attractive site (a tolerant region) for introducing structurally diverse moieties to generate novel molecules with reasonable anti-HIV activity (Fig. 2).

These backgrounds prompted us to further explore novel 4-(2-naphthoyl) TTAs bearing substituted anilide phenyl ring or heterocycles linked with the amide. In this paper, a series of novel TTA analogues were synthesized and evaluated for anti-HIV activity in MT-4 cell culture.