Indolyl Aryl Sulfones bearing Natural and Unnatural Aminoacids. Discovery of the First Class of Non-Nucleoside Dual Inhibitors of HIV-1 Wild Type and Resistant Mutant Strains Reverse Transcriptase, and Coxsackie B4 Virus.

New potent indolyl aryl sulfone (IAS) HIV-1 NNRTIs were obtained by coupling natural and unnatural aminoacids to the 2-carboxamide, and introducing different electron-withdrawing substituent(s) at the position(s) 4 and 5 of the indole nucleus. The new IASs inhibited the HIV-1 replication in human T-lymphocyte (CEM) cells at low/sub-nanomolar concentration, and were weakly cytostatic. Against the mutant L100I and K103N RT HIV-1 strain, sulfones 3, 4, 19, 27 and 31 were superior to EFV, and equipotent to MKC-4965 and TMC120, and were as potent as EFV against the mutant Y181C strain. The new IASs proved to be effective inhibitors of Coxackie B4 virus with an EC50 = 2 M. In view of this particular therapeutic profile, these agents might be useful for the treatment of HIV seropositive patients with pathological conditions associated Coxsackie B virus. Superimposition of PLANTS docked conformations of 19 and the highly active derivative 9 revealed different hydrophobic interactions of the 3,5-dimethylphenyl group, for which a staking interaction with Tyr181 aromatic side chain was observed. In L100I mutated RT the mutation of leucine to isoleucine does not affect the binding mode confirming all the interactions reported for the WT strain.