Thiadiazoline- and Pyrazoline-Based Carboxamides and Carbothioamides: Synthesis and Inhibition against Nitric Oxide Synthase

M Encarnación Camacho,Fabio Arias,Miguel Romero,Miguel A Gallo,Meriem Chayah,M Dora Carrión,Juan Duarte

doi:10.1155/2018/9242616

Abstract

Two new families of pyrazoline and thiadiazoline heterocycles have been developed. Their inhibitory activities against two different isoforms of nitric oxide synthase (inducible and neuronal NOS) are reported. The novel derivatives were synthesized combining the arylthiadiazoline or arylpyrazoline skeleton and a carboxamide or carbothioamide moiety, used as starting material ethyl 2-nitrobenzoates or substituted nitrobenzaldehydes, respectively. The structure-activity relationships of final molecules are discussed in terms of the R1 radical effects in the aromatic ring, the Y atom in the heterocyclic system, the X heteroatom in the main chain, and the R2 substituent in the carboxamide or carbothioamide rest. In general, thiadiazolines (5a–e) inhibit preferentially the neuronal isoform; among them, 5a is the best nNOS inhibitor (74.11% at 1 mM, IC50 = 420 μM). In contrast, pyrazolines (6a–r) behave better as iNOS than nNOS inhibitors, 6m being the best molecule of this series (76.86% at 1 mM of iNOS inhibition, IC50 = 130 μM) and the most potent of all tested compounds.

Highlights

Heterocyclic rings having two or three heteroatoms in their skeleton have been widely described as part of pharmacological agents with interesting therapeutic applications
Scheme 1 shows the general synthetic pathway of the final 5-(2-amino-5-phenylsubstituted)-2,2-dimethyl-Nsubstituted-1,3,4-thiadiazole-3(3H)-carboxamide derivatives a–e described in the present report
Nucleophilic addition of alkyl or arylisocyanate to these last compounds using microwave gave the nitrophenyl thiadiazole-carboxamides a–e [37], which were subjected to reduction in the presence of stannous chloride in refluxing ethanol [38] to give the desired aminoaryl thiadiazole-carboxamides a–e

Summary

Introduction

Heterocyclic rings having two or three heteroatoms in their skeleton have been widely described as part of pharmacological agents with interesting therapeutic applications In this way, thiadiazoline system is part of structures with antileishmanial activity [1], as well as antimicrobial [2], antiinflammatory [2, 3], anticonvulsant [4], or antitumoral [5, 6]. Heterocyclic pyrazoline shows a wide spectrum of pharmacological properties such as anticancer [7,8,9], antiinflammatory [10], anticonvulsant [11, 12], antimicrobial [13], antibacterial, antifungal, and antiparasitic [14] These two types of heterocycles have been recognized as nitric oxide synthase (NOS) inhibitors that could be useful in neurodegenerative diseases and inflammatory arthritis [15,16,17,18,19]. Three isoforms of NOS have been identified; two of them are constitutively expressed: neuronal (nNOS), which takes part in neural signaling, and endothelial (eNOS), involved in the systemic blood pressure control and plateled aggregation inhibition; the third isoform, inducible NOS (iNOS), is expressed during immune activation and plays an important role in inflammatory response [23]

Methods

Results

Conclusion