title: Natural product-inspired esters and amides of ferulic and caffeic acid as dual inhibitors of HIV-1 reverse transcriptase.
abstract: Using an HIV-1 Reverse Transcriptase (RT)-associated RNase H inhibition assay as lead, bioguided fractionation of the dichloromethane extract of the Ocimum sanctum leaves led to the isolation of five triterpenes (1-5) along with three 3-methoxy-4-hydroxy phenyl derivatives (6-8). The structure of this isolates were determined by 1D and 2D NMR experiments as well as ESI-MS. Tetradecyl ferulate (8) showed an interesting RNase H IC50value of 12.4 μM and due to the synthetic accessibility of this secondary metabolite, a structure-activity relationship study was carried out. A series of esters and amides of ferulic and caffeic acids were synthesized and, among all, the most active was N-oleylcaffeamide displaying a strong inhibitory activity towards both RT-associated functions, ribonuclease H and DNA polymerase. Molecular modeling studies together with Yonetani-Theorell analysis, demonstrated that N-oleylcaffeamide is able to bind both two allosteric site located one close to the NNRTI binding pocket and the other close to RNase H catalytic site.
authors.affiliation: Department of Life and Environmental Sciences, Drug Sciences Section, University of Cagliari, via Ospedale 72, 09124 Cagliari, Italy.
authors.forename: Vijay P
authors.initials: VP
authors.lastname: Sonar
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella di Monserrato SS554, 09042, Monserrato, Cagliari, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Corona
authors.affiliation: Department of Life and Environmental Sciences, Drug Sciences Section, University of Cagliari, via Ospedale 72, 09124 Cagliari, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Distinto
authors.affiliation: Department of Life and Environmental Sciences, Drug Sciences Section, University of Cagliari, via Ospedale 72, 09124 Cagliari, Italy.
authors.forename: Elias
authors.initials: E
authors.lastname: Maccioni
authors.affiliation: Department of Life and Environmental Sciences, Drug Sciences Section, University of Cagliari, via Ospedale 72, 09124 Cagliari, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Meleddu
authors.affiliation: Department of Life and Environmental Sciences, Drug Sciences Section, University of Cagliari, via Ospedale 72, 09124 Cagliari, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Fois
authors.affiliation: Dipartimento di Scienze Chimiche, University of Cagliari, Cittadella di Monserrato, 09042, Monserrato, Cagliari, Italy.
authors.forename: Costantino
authors.initials: C
authors.lastname: Floris
authors.affiliation: Department of Botany, S. S. G. M. College, IN-423601 Kopargaon, District Ahmednagar, MS, India.
authors.forename: Nilesh V
authors.initials: NV
authors.lastname: Malpure
authors.affiliation: Dipartimento di Scienze della Salute, Università"Magna Græcia" di Catanzaro, Campus "S. Venuta", Viale Europa, 88100 Catanzaro, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella di Monserrato SS554, 09042, Monserrato, Cagliari, Italy.
authors.forename: Enzo
authors.initials: E
authors.lastname: Tramontano
authors.affiliation: Department of Life and Environmental Sciences, Drug Sciences Section, University of Cagliari, via Ospedale 72, 09124 Cagliari, Italy. Electronic address: cottiglf@unica.it.
authors.forename: Filippo
authors.initials: F
authors.lastname: Cottiglia
mesh_terms: D000577:Amides / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002109:Caffeic Acids / Q000494:pharmacology*; D003373:Coumaric Acids / Q000737:chemistry / Q000494:pharmacology*; D004259:DNA-Directed DNA Polymerase / Q000187:drug effects; D004952:Esters / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D010936:Plant Extracts / Q000737:chemistry; D054309:Ribonuclease H, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014315:Triterpenes
chemical_list: D000577:Amides; D019380:Anti-HIV Agents; D002109:Caffeic Acids; D003373:Coumaric Acids; D004952:Esters; D010936:Plant Extracts; D014315:Triterpenes; C004999:ferulic acid; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D004259:DNA-Directed DNA Polymerase; D054309:Ribonuclease H, Human Immunodeficiency Virus; C040048:caffeic acid
keywords: Ferulic acid derivatives; HIV-1; Ocimum sanctum; RNase H; Reverse transcriptase; Triterpenes