Design, Synthesis and Biological Evaluation of Novel N-Alkyl-4-Methyl-2,2- Dioxo-1H-2λ6,1-Benzothiazine-3-Carboxamides as Promising Analgesics

Abstract

Introduction: An analysis of the literature on the painkillers long used in traditional medicine, which are isolated from plant materials, has shown that many of them are alkylamides of various carboxylic acids. This fact served as the basis for the study of a large group of N-alkyl-4- methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3-carboxamides as potential new analgesics. The objects of the study were synthesized in the traditional way involving the initial conversion of 4-methyl- 2,2-dioxo-1H-2λ⁶,1- benzothiazine-3-carboxylic acid to imidazolide, in which imidazolide was used as an acylating agent. The method is simple to implement and, as a rule, gives high yields of final alkylamides. However, in reaction with sterically hindered tert-butylamine, along with the "normal" product, an unexpected formation of N-tert-butyl-4-methyl-1-(4-methyl-2,2-dioxo-1H-2λ⁶,1- benzothiazine-3-carbonyl)-2,2-dioxo-2λ⁶,1-benzothiazine-3-carboxamide was observed, which was characterized by X-ray diffraction analysis as a monosolvate with N,N-dimethylformamide. These synthetic problems can be avoided using a more powerful acylating agent, 4-methyl-2,2-dioxo-1H- 2λ⁶,1- benzothiazine-3-carbonyl chloride.

Background: A large group of new N-alkyl-4-methyl-2,2-dioxo-1H-2λ⁶,1-benzothiazine-3- carboxamides was synthesized.

Objective: On the basis of molecular docking, some derivatives of N-alkyl-4-methyl-2,2-dioxo-1H- 2λ⁶,1-benzothiazine-3-carboxamides have been designed. Their preliminary structure-activity relationships (SAR) have been studied. The most rational approaches to the synthesis of lead compounds have been developed. The most active compounds have shown high anti-inflammatory and analgesic activities.

Methods: The structure of all compounds prepared has been confirmed by the data of elemental analysis, 1H- and 13C NMR spectroscopy, and electrospray ionization liquid chromato-mass spectrometry. For rational drug design, optimization of further pharmacological screening and prediction of a possible mechanism of pharmacological action, molecular docking has been performed. For the determination of activity, pharmacological studies have been carried out.

Results: Pharmacological tests have determined that the transition from N-aryl(heteroaryl) alkylamides to "pure" N-alkylamides we carried out is accompanied by a significant reduction and even complete loss of anti-inflammatory effect with remaining analgesic activity.

Conclusion: According to the studies, compounds from N-alkyl-4-methyl-2,2-dioxo-1H-2λ⁶,1- benzothiazine-3-carboxamides are potential anti-inflammatory and analgesic agents.

Keywords: Benzothiazine-3-carboxamide; alkyl amides; analgesic activity; anti-inflammatory action; crystal structure; cyclooxygenase-2.