title: De novo design and synthesis of HIV-1 integrase inhibitors.
abstract: Existing AIDS therapies are out of reach for most HIV-infected people in developing countries and, where available, they are limited by their toxicity and their cost. New anti-HIV agents are needed urgently to combat emerging viral resistance and reduce the side effects associated with currently available drugs. Toward this end, LeapFrog, a de novo drug design program was used to design novel, potent, and selective inhibitors of HIV-1 integrase. The designed compounds were synthesized and tested for in vitro inhibition of HIV-1 integrase. Out of the 25 compounds that were designed, and synthesized, four molecules (compounds 23, 26, 43, and 59) showed moderate to low inhibition of HIV-1 integrase for 3'-processing and 3'-strand transfer activities. Nonetheless, these compounds possess structural features not seen in known HIV-1 integrase inhibitors and thus can serve as excellent leads for further optimization of anti-HIV-1 integrase activity.
authors.affiliation: Pharmaceutical Division, Department of Chemical Technology, University of Mumbai, Matunga, Mumbai 400019, India. m.makhija@exchange.curtin.edu.au
authors.forename: Mahindra T
authors.initials: MT
authors.lastname: Makhija
authors.forename: Rajesh T
authors.initials: RT
authors.lastname: Kasliwal
authors.forename: Vithal M
authors.initials: VM
authors.lastname: Kulkarni
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology; D016018:Least-Squares Analysis; D008958:Models, Molecular; D008968:Molecular Conformation; D013057:Spectrum Analysis
chemical_list: D019428:HIV Integrase Inhibitors