2-amino-6-arylsulfonylbenzonitriles as non-nucleoside reverse transcriptase inhibitors of HIV-1

series of 2-amino-5-arylthiobenzonitriles (1) was found to be active agains t 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 analog ues, a number having activity against HIV-1 in the nanomolar range. Structu ral-activity relationship (SAR) studies suggested that a meta substituent, particularly a meta methyl substituent, invariably increased antiviral acti vities. 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 compou nds 3v, 3w, 3x, and 3y having IC50 values against HIV-1 in the low nanomola r range. When gauged for their broad-spectrum antiviral activity against ke y non-nucleoside reverse transcriptase inhibitor (NNRTI) related mutants, a ll the di-meta-substituted sulfones 3u-z and the 2-naphthyl analogue 3ee ge nerally 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 o f the complex of 3v (739W94) in HIV-1 reverse transcriptase showed an overl ap in the binding domain when compared with the complex of nevirapine in HI V-1 reverse transcriptase. The X-ray structure allowed for the rationalizat ion of SAR data and potencies of the compounds against the mutants.