Arylazolyl(azinyl)thioacetanilides: Part 19: Discovery of Novel Substituted Imidazo[4,5‐b]pyridin‐2‐ylthioacetanilides as Potent HIV NNRTIs Via a Structure‐based Bioisosterism Approach

Abstract

With the continuation of our unremitting efforts toward the discovery of potent HIV-1 NNRTIs, a series of novel imidazo[4,5-b]pyridin-2-ylthioacetanilides were designed, synthesized, and evaluated for their antiviral activities through combining bioisosteric replacement and structure-based drug design. Almost all of the title compounds displayed moderate to good activities against wild-type (wt) HIV-1 strain with EC50 values ranging from 0.059 to 1.41 μm in a cell-based antiviral assay. Thereinto, compounds 12 and 13 were the most active two analogues possessing an EC50 value of 0.059 and 0.073 μm against wt HIV-1, respectively, which was much more effective than the control drug nevirapine (EC50 = 0.26 μm) and comparable to delavirdine (EC50 = 0.038 μm). In addition, one selected compound showed a remarkable reverse transcriptase inhibitory activity compared to nevirapine and etravirine. In the end of this manuscript, preliminary structure-activity relationships (SARs) and molecular modeling studies were detailedly discussed, which may provide valuable insights for further optimization.

Recent Advances in the Design and Development of Non‐nucleoside Reverse Transcriptase Inhibitor Scaffolds

“…The cyclopropylnaphthalene moiety of RDEA-806 was preserved, and several substituents were introduced into the phenyl ring of acetanilide. [42] Amongt he prepared analogues, 66 a and 66 b were found to be more potent than others against the wild-type HIV-1 strain ( Table 2).…”

“…Based on these results, further research on the central heterocyclic core was performed using the structure‐based drug design and bioisosteric replacement. The cyclopropylnaphthalene moiety of RDEA‐806 was preserved, and several substituents were introduced into the phenyl ring of acetanilide . Among the prepared analogues, 66 a and 66 b were found to be more potent than others against the wild‐type HIV‐1 strain (Table ).…”

Synthesis and antiviral activity of diverse heterocyclic scaffolds

“…Substituion of methyl groups in 3 and 5 positions of both phenyl groups at C-6 and C-7 of the coumarin ring in 33a and substitution of methyl group in 3-position of phenyl residue at C-7 together with the triflate at C-6 of the coumarin ring in 34f considerably helped in enhancing their anti-HIV activity. Li et al (2016) have designed the synthesis of a series of imidazo [4,5-b]pyridin-2-ylthioacetanilides 41a-k and 42a-d through combining bioisosteric replacement and structure-based drug designing approach (Scheme 4) and were evaluated as potent HIV-I NNRTIs. Compounds 41c and 41d were found to be the promising leads with better inhibitory activities against HIV-I (IIIB) with EC 50 value of 0.059 and 0.073 μM, respectively.…”

Pharmacological Potential and Synthetic Approaches of Imidazo[4,5-b]pyridine and Imidazo[4,5-c]pyridine Derivatives

“…The presence of electron-withdrawing group in the ortho position of the anilide moiety is likewise relevant for anti-HIV activity. Derivatives 25 and 26 were characterized by higher potency than the reference drugs nevirapine and delaviridine [ 56 ].…”