2-Amino-6-arylsulfonylbenzonitriles as Non-nucleoside Reverse Transcriptase Inhibitors of HIV-1

Abstract

A series of 2-amino-5-arylthiobenzonitriles (1) was found to be active against HIV-1. Structural modifications led to the sulfoxides (2) and sulfones (3). The sulfoxides generally showed antiviral activity against HIV-1 similar to that of 1. The sulfones, however, were the most potent series of analogues, a number having activity against HIV-1 in the nanomolar range. Structural-activity relationship (SAR) studies suggested that a meta substituent, particularly a meta methyl substituent, invariably increased antiviral activities. However, optimal antiviral activities were manifested by compounds where both meta groups in the arylsulfonyl moiety were substituted and one of the substituents was a methyl group. Such a disubstitution led to compounds 3v, 3w, 3x, and 3y having IC50 values against HIV-1 in the low nanomolar range. When gauged for their broad-spectrum antiviral activity against key non-nucleoside reverse transcriptase inhibitor (NNRTI) related mutants, all the di-meta-substituted sulfones 3u-z and the 2-naphthyl analogue 3ee generally showed single-digit nanomolar activity against the V106A and P236L strains and submicromolar to low nanomolar activity against strains E138K, V108I, and Y188C. However, they showed a lack of activity against the K103N and Y181C mutant viruses. The elucidation of the X-ray crystal structure of the complex of 3v (739W94) in HIV-1 reverse transcriptase showed an overlap in the binding domain when compared with the complex of nevirapine in HIV-1 reverse transcriptase. The X-ray structure allowed for the rationalization of SAR data and potencies of the compounds against the mutants.

Classical QSAR Modeling of HIV‐1 Reverse Transcriptase Inhibitor 2‐Amino‐6‐arylsulfonylbenzonitriles and Congeners

“…The above equations show that for both response variables, presence of sulfone moiety contributes significantly to the activities, which is in accordance with the report [21] that sulfonyl oxygens maintain Tyr181 side chain of the binding site of RT in the proper position for optimum interaction with the ligand. Further, molar refractivity of meta substituents plays a significant role in both the cases: second meta substituents potentiate the activities probably due to enhanced binding (presumably through dispersion interaction) of the ligand with the binding site.…”

“…Further, molar refractivity of meta substituents plays a significant role in both the cases: second meta substituents potentiate the activities probably due to enhanced binding (presumably through dispersion interaction) of the ligand with the binding site. This is further corroborated by the X-ray crystal structures of the complex of HIV-1 RT with non-nucleoside inhibitors [21], which clearly shows that the binding site can favorably accommodate the meta substituents. Again, presence of metatrifluoromethyl group at the aryl ring is detrimental for both the activity parameters.…”

“…The Anti-HIV-1 activity (assayed in MT-4 cell line) and RT binding affinity data [IC 50 (mm)] of the compounds [21] were converted to the logarithmic scale [pC(mM)] and then used for subsequent QSAR analyses as the response variable. The activity data (Table 1) were subjected to QSAR analysis using linear free energy related (LFER) model of Hansch [22,23] using lipophilicity (p), electronic parameter (Hammett s) and steric (molar refractivity MR) parameters of the aryl ring substituents along with appropriate dummy parameters as predictor variables.…”

“…Recently, Chan et al [21] have reported a series of 2-amino-6-arylsulfonylbenzonitriles and their thio and sulfinyl congeners as potential anti-HIV-1 compounds. The present study attempts to explore QSAR of anti-HIV-1 activity and HIV-1 reverse transcriptase (RT) binding affinity of the compounds using classical QSAR tools in order to give quantitative physical organic chemistry basis to the structure-activity relations.…”

Conformational Changes in HIV-1 Reverse Transcriptase Induced by Nonnucleoside Reverse Transcriptase Inhibitor Binding

“…[ 12,13,16,19,26,27,28,29,35,37,45,46,47,48,49,50,51]. This wealth of structural data has provided considerable insight into HIV-1 RT molecular structure including: (i) the precise location of the DNA polymerase and RNase H active sites; (ii) key amino acid residues involved in substrate binding; (iii) the precise location of the NNRTI binding pocket (NNRTI-BP); (iv) mechanisms of HIV-1 resistance to NRTI and NNRTI; and (v) conformational changes associated with both substrate and NNRTI binding.…”