Development of Urea and Thiourea Kynurenamine Derivatives: Synthesis, Molecular Modeling, and Biological Evaluation as Nitric Oxide Synthase Inhibitors

• Published in: ChemMedChem Vol. 10; no. 5; pp. 874 - 882
• Main Authors: Chayah, Mariem, Carrión, M. Dora, Gallo, Miguel A., Jiménez, Rosario, Duarte, Juan, Camacho, M. Encarnación
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.05.2015; WILEY‐VCH Verlag; Wiley; Wiley Subscription Services, Inc
• Subjects: Animals; biological activity; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; inhibitors; Kynuramine - analogs & derivatives; Kynuramine - chemistry; Kynuramine - pharmacology; kynurenamines; Life Sciences & Biomedicine; Male; Models, Molecular; molecular modeling; Molecular Structure; Nitric oxide; Nitric Oxide - analysis; nitric oxide synthase; Nitric Oxide Synthase Type I - antagonists & inhibitors; Nitric Oxide Synthase Type I - metabolism; Nitric Oxide Synthase Type II - antagonists & inhibitors; Nitric Oxide Synthase Type II - metabolism; Pharmacology & Pharmacy; Rats; Rats, Wistar; Science & Technology; Structure-Activity Relationship; Urea - analogs & derivatives; Urea - chemistry; kynurenamines; inhibitors; biological activity; MELATONIN; SPECIFICITY; NNOS ACTIVITY; STRUCTURE-ACTIVITY DEPENDENCE; KYNURENINES; 4,5-DIHYDRO-1H-PYRAZOLE DERIVATIVES; INDUCTION; INOS; molecular modeling; DISEASE; nitric oxide synthase; RAT-BRAIN
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201500007

Herein we describe the synthesis of a new family of kynurenamine derivatives with a urea or thiourea moiety, together with their in vitro biological evaluation as inhibitors of both neuronal and inducible nitric oxide synthases (nNOS and iNOS, respectively), enzymes responsible for the biogenesis of NO. These compounds were synthesized from a 5‐substituted‐2‐nitrophenyl vinyl ketone scaffold in a five‐step procedure with moderate to high chemical yields. In general, the assayed compounds show greater inhibition of iNOS than of nNOS, with 1‐[3‐(2‐amino‐5‐chlorophenyl)‐3‐oxopropyl]‐3‐ethylurea (compound 5 n) being the most potent iNOS inhibitor in the series and the most iNOS/nNOS‐selective compound. In this regard, we performed molecular modeling studies to propose a binding mode for this family of compounds to both enzymes and, thereby, to elucidate the differential molecular features that could explain the observed selectivity between iNOS and nNOS. Urea‐lly must see this: A series of urea and thiourea kynurenamine derivatives were synthesized and evaluated for their inhibitory activities against NOS. One urea compound was identified as the most potent iNOS inhibitor and the most iNOS/nNOS‐selective. Docking studies confirmed the best orientation and interaction of this compound inside the inducible isoform.