Novel modifications in the series of O-(2-phthalimidoethyl)-N-substituted thiocarbamates and their ring-opened congeners as non-nucleoside HIV-1 reverse transcriptase inhibitors

SPALLAROSSA A;CESARINI S;RANISE A;BRUNO O;SCHENONE S;LA COLLA P;COLLU, GABRIELLA;SANNA, GIUSEPPINA;SECCI, BARBARA;LODDO, ROBERTA

2009-01-01

---

Abstract

The structure–activity relationships (SARs) of N-aryl-O-(2-phthalimidoethyl)thiocarbamates (C-TCs) and their imide ring-opened congeners (O-TCs) as non-nucleoside HIV-1 reverse transcriptase inhibitors were further investigated. The SAR strategy involved modifications of the N-phenyl ring followed by the hybridization of the most promising N-aryl and O-(2-phthalimidoethyl) substructures. The role of stereochemistry and tert-butyl substitution of the phthalimidoethyl moiety on activity was also investigated. Seventy-six analogues were prepared by parallel solution-phase synthesis. Twenty-two C-TCs displayed nanomolar activity against wild-type HIV-1 and a number of analogues were effective against the Y181C mutant. Compound 56 combined the highest activity so far identified against Y181C (EC50 ¼1.3 mM) with good potency against the K103R mutant (EC50¼ 4.8 mM). Docking simulations helped to rationalize the SARs.