title: Notable difference in anti-HIV activity of integrase inhibitors as a consequence of geometric and enantiomeric configurations.
abstract: While some examples are known of integrase inhibitors that exhibit potent anti-HIV activity, there are very few cases reported of integrase inhibitors that show significant differences in anti-HIV activity that result from distinctions in cis- and trans-configurations as well as enantiomeric stereostructure. We describe here the design and synthesis of two enantiomeric trans-hydroxycyclopentyl carboxamides which exhibit notable difference in anti-HIV activity. This difference is explained through their binding interactions within the active site of the HIV-1 integrase intasome. The more active enantiomer 3 (EC50 25nM) was relatively stable in human liver microsomes. Kinetic data revealed that its impact on key cytochrome P450 isozymes, as either an inhibitor or an activator, was minor, suggesting a favorable CYP profile.
authors.affiliation: UGA Center for Drug Discovery, the College of Pharmacy, R.C. Wilson Pharmacy Bldg., Room 320, University of Georgia, Athens, GA 30602, USA.
authors.forename: Maurice
authors.initials: M
authors.lastname: Okello
authors.forename: Sanjay
authors.initials: S
authors.lastname: Mishra
authors.forename: Malik
authors.initials: M
authors.lastname: Nishonov
authors.forename: Vasu
authors.initials: V
authors.lastname: Nair
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology* / Q000502:physiology; D006801:Humans; D007651:Keto Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D014779:Virus Replication / Q000187:drug effects
chemical_list: C585740:4-(5-(2,4-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-N-(2-hydroxycyclopentyl)but-3-enamide; D019428:HIV Integrase Inhibitors; D007651:Keto Acids; D011728:Pyridones; D003577:Cytochrome P-450 Enzyme System; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1