Synthesis, bioevaluation and docking studies of new imidamide derivatives as nitric oxide synthase inhibitors

Fabio Arias; Francisco Franco-Montalban; Miguel Romero; M Dora Carrión; M Encarnación Camacho

doi:10.1016/j.bmc.2021.116294

Synthesis, bioevaluation and docking studies of new imidamide derivatives as nitric oxide synthase inhibitors

Bioorg Med Chem. 2021 Aug 15:44:116294. doi: 10.1016/j.bmc.2021.116294. Epub 2021 Jun 28.

Authors

Fabio Arias¹, Francisco Franco-Montalban¹, Miguel Romero², M Dora Carrión³, M Encarnación Camacho⁴

Affiliations

¹ Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, Spain.
² Departamento de Farmacología, Facultad de Farmacia, Universidad de Granada, Spain; Instituto de Investigación Biosanitaria de Granada, ibs.GRANADA, Granada, Spain; Department of Pharmacology, School of Pharmacy and Center for Biomedical Research (CIBM), University of Granada, 18071 Granada, Spain; Ciber de Enfermedades Cardiovasculares (CIBERCV), Spain.
³ Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, Spain. Electronic address: dcarrion@ugr.es.
⁴ Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, Spain. Electronic address: ecamacho@ugr.es.

PMID: 34218000
DOI: 10.1016/j.bmc.2021.116294

Abstract

In search of new Nitric Oxide Synthase (NOS) inhibitor agents, two isosteric series of derivatives with an imidamide scaffold (one of them with a hydroxyl group and the other with a carbonyl one) were synthesized and evaluated on inducible (iNOS) and neuronal (nNOS) isoforms. These compounds have been designed by combining a kynurenamine framework with an amidine moiety in order to improve selectivity for the inducible isoform. In general, the in vitro inhibitory assays exhibited better inhibition values on the iNOS isoform, being the N-(3-(2-amino-5-methoxyphenyl)-3-hydroxypropyl)-4-(trifluoromethyl)benzimidamide 4i the most active inhibitor with the highest iNOS selectivity, without inhibiting eNOS. Docking studies on the two most active compounds suggest a different binding mode on both isozymes, supporting the experimentally observed selectivity towards the inducible isoform. Physicochemical in silico studies suggest that these compounds possess good drug-likeness properties.

Keywords: Drug design; Imidamides; Inhibitors; Nitric Oxide Synthase; Synthesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amidines / chemical synthesis
Amidines / chemistry
Amidines / pharmacology*
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Molecular Docking Simulation*
Molecular Structure
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
Structure-Activity Relationship

Substances

Amidines
Enzyme Inhibitors
NOS1 protein, human
NOS2 protein, human
Nitric Oxide Synthase Type I
Nitric Oxide Synthase Type II