Studies on Cycloheptathiophene‐3‐carboxamide Derivatives as Allosteric HIV‐1 Ribonuclease H Inhibitors

Abstract

Despite the significant progress achieved with combination antiretroviral therapy in the fight against human immunodeficiency virus (HIV) infection, the difficulty to eradicate the virus together with the rapid emergence of multidrug-resistant strains clearly underline a pressing need for innovative agents, possibly endowed with novel mechanisms of action. In this context, owing to its essential role in HIV genome replication, the reverse transcriptase associated ribonuclease H (RNase H) has proven to be an appealing target. To identify new RNase H inhibitors, an in-house cycloheptathiophene-3-carboxamide library was screened; this led to compounds endowed with inhibitory activity, the structural optimization of which led to the catechol derivative 2-(3,4-dihydroxybenzamido)-N-(pyridin-2-yl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide (compound 33) with an IC50 value on the RNase H activity in the nanomolar range. Mechanistic studies suggested selective inhibition of the RNase H through binding to an innovative allosteric site, which could be further exploited to enrich this class of inhibitors.

Exploring the cycloheptathiophene-3-carboxamide scaffold to disrupt the interactions of the influenza polymerase subunits and obtain potent anti-influenza activity

“…All the reported values represent the means ± SD of data derived from at least three independent experiments in duplicate. d Reported in reference [26].…”

“…isopropyl, tert-butyl, cyclohexyl, piperazine, and 2-pyridilpiperazine (12)(13)(14)(15)(16), were also used as C-3 substituents. Methoxy intermediates 17 [26], 18, and 19 (Table 1) were also assayed to enrich the SAR. The replacement of the hydroxyl group at the C-2 phenyl ring was also investigated with the o-amino and p-amino derivatives 20 [26] and 21 [26] (Table 1).…”

“…Methoxy intermediates 17 [26], 18, and 19 (Table 1) were also assayed to enrich the SAR. The replacement of the hydroxyl group at the C-2 phenyl ring was also investigated with the o-amino and p-amino derivatives 20 [26] and 21 [26] (Table 1).…”

“…Chemical shifts were recorded in ppm (δ) and the spectral data are consistent with the assigned structures. The spin multiplicities are indicated by the symbols s (singolet), d (doublet), t (triplet), q (quartet), m (multiplet), and bs (broad singolet).The synthesis of some compounds reported in this study, i.e., 17[26], 20[26], 21[26], 24[27], 28[27], 32[18], 33[29], and 46[30], has been previously described.…”

Biological evaluation of molecules of the azaBINOL class as antiviral agents: Inhibition of HIV-1 RNase H activity by 7-isopropoxy-8-(naphth-1-yl)quinoline

“…Several classes of compounds have shown promising antiviral activity by acting on RNase H activity including N-hydroxyimides, 42 tropolones, 43,44 hydroxypyridonecarboxylic acids, 25,45,46 diketoacids, 47 vinylogous ureas, 48 and thienopyrimidinones; 49 48,51 as well as cycloheptathiophene-3-carboxamides (cHTC). 52,53 Allosteric binding may exhibit fewer side effects compared to active site Mg 2+ chelating inhibitors and therefore allow for a more favorable therapeutic window. 8, 9…”