Novel Cyclopropyl-Indole Derivatives as HIV Non-Nucleoside Reverse Transcriptase Inhibitors

Mohammad Hassam; Adriaan E Basson; Dennis C Liotta; Lynn Morris; Willem A L van Otterlo; Stephen C Pelly

doi:10.1021/ml3000462

Novel Cyclopropyl-Indole Derivatives as HIV Non-Nucleoside Reverse Transcriptase Inhibitors

ACS Med Chem Lett. 2012 May 2;3(6):470-5. doi: 10.1021/ml3000462. eCollection 2012 Jun 14.

Authors

Mohammad Hassam¹, Adriaan E Basson², Dennis C Liotta³, Lynn Morris², Willem A L van Otterlo¹, Stephen C Pelly¹

Affiliations

¹ Department of Chemistry and Polymer Science, Stellenbosch University , Western Cape, South Africa.
² National Institute for Communicable Diseases , Johannesburg, South Africa.
³ Department of Chemistry, Emory University , Atlanta, Georgia, United States.

Abstract

The HIV pandemic represents one of the most serious diseases to face mankind in both a social and economic context, with many developing nations being the worst afflicted. Due to ongoing resistance issues associated with the disease, the design and synthesis of anti-HIV agents presents a constant challenge for medicinal chemists. Utilizing molecular modeling, we have designed a series of novel cyclopropyl indole derivatives as HIV non-nucleoside reverse transcriptase inhibitors and carried out their preparation. These compounds facilitate a double hydrogen bonding interaction to Lys101 and efficiently occupy the hydrophobic pockets in the regions of Tyr181/188 and Val179. Several of these compounds inhibited HIV replication as effectively as nevirapine when tested in a phenotypic assay.

Keywords: HIV; NNRTI; cyclopropyl; indole; rational design.