Molecular modeling, synthesis, and in vitro/in vivo evaluation of 1,4-dihydropyridine, pyrrole, and benzopyran analogs as HIV-1 RT inhibitors

MEDI 92

Tanaji T Talele, talelet@stjohns.edu1, Dinesh Manvar, NA2, Kena Raval, NA2, Virendra N Pandey, pandey@umdnj.edu3, and Anamik Shah, anamik_shah@hotmail.com2. (1) Department of Pharmaceutical Sciences, College of Pharmacy & Allied Health Professions, St. John's University, 8000 Utopia Parkway, Jamaica, NY 11439, (2) Department of Chemistry, Saurashtra University, University Road, Rajkot, 360005, India, (3) Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey, 185 South Orange Ave, Newark, NJ 07103
The reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1) is a major target of current antiretroviral drug therapy for the treatment of AIDS. Non-nucleoside RT inhibitors (NNRTIs) interact with a specific pocket of HIV-1 RT (the nonnucleoside inhibitor binding pocket, NNIBP) that is close to, but distinct from, the nucleoside RT inhibitor (NRTI) binding pocket. Molecular modeling studies based on the X-ray structure of a complex of HIV-1 RT with nevirapine (PDB ID: 1VRT), suggested the synthesis of novel 1,4-dihydropyridine, pyrrole, and benzopyran analogues whose HIV-1 RT inhibitory activity was assessed using in vitro and in vivo assays. The new analogues exhibited Ki value in the range of 1.4 µM to 2.3 µM. These analogues were found to be less toxic than efavirenz and nevirapine in CEM cells as judged by their CC50 values. The synthesis, biological activity, cytotoxicity, and induced-fit docking results will be discussed in detail.
 

Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007