Department of Pharmaceutical Chemistry, National University of Pharmacy, 53 Pushkinska st., 61002 Kharkiv, Ukraine.
Department of Pharmacology, N.I. Pirogov Vinnitsa National Medical University, 56 Pirogov st., 21018 Vinnitsa, Ukraine.
Med Chem. 2023;19(2):174-192. doi: 10.2174/1573406418666220820103927.
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-2λ,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-2λ,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-2λ,1- benzothiazine-3-carbonyl)-2,2-dioxo-2λ,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- 2λ,1- benzothiazine-3-carbonyl chloride.
A large group of new N-alkyl-4-methyl-2,2-dioxo-1H-2λ,1-benzothiazine-3- carboxamides was synthesized.
On the basis of molecular docking, some derivatives of N-alkyl-4-methyl-2,2-dioxo-1H- 2λ,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.
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.
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.
According to the studies, compounds from N-alkyl-4-methyl-2,2-dioxo-1H-2λ,1- benzothiazine-3-carboxamides are potential anti-inflammatory and analgesic agents.
对长期以来在传统医学中使用的、从植物材料中分离出来的止痛药的文献进行分析表明，其中许多是各种羧酸的烷基酰胺。这一事实为研究一大类 N-烷基-4-甲基-2,2-二氧代-1H-2λ,1-苯并噻嗪-3-甲酰胺作为潜在的新型镇痛药提供了依据。本文以传统的方法合成了这些化合物，最初是将 4-甲基-2,2-二氧代-1H-2λ,1-苯并噻嗪-3-羧酸转化为咪唑啉，其中咪唑啉作为酰化剂。该方法实施简单，通常能得到较高产率的最终烷基酰胺。然而，在与空间位阻较大的叔丁胺反应时，除了“正常”产物外，还观察到了意想不到的 N-叔丁基-4-甲基-1-(4-甲基-2,2-二氧代-1H-2λ,1-苯并噻嗪-3-羰基)-2,2-二氧代-2λ,1-苯并噻嗪-3-甲酰胺的形成，通过 X 射线衍射分析将其鉴定为具有 N,N-二甲基甲酰胺的单溶剂化物。这些合成问题可以通过使用更强大的酰化剂 4-甲基-2,2-二氧代-1H-2λ,1-苯并噻嗪-3-羰基氯来避免。
合成了一大类新型 N-烷基-4-甲基-2,2-二氧代-1H-2λ,1-苯并噻嗪-3-甲酰胺。
基于分子对接，设计了一些 N-烷基-4-甲基-2,2-二氧代-1H-2λ,1-苯并噻嗪-3-甲酰胺衍生物。研究了它们的初步构效关系(SAR)。开发了最合理的合成先导化合物的方法。最有效的化合物表现出了高抗炎和镇痛活性。
所有合成化合物的结构均通过元素分析、1H 和 13C NMR 光谱以及电喷雾电离液质联用数据得到证实。为了进行合理的药物设计、优化进一步的药理筛选和预测可能的药理作用机制，进行了分子对接。为了确定活性，进行了药理学研究。
药理试验确定，我们进行的从 N-芳基(杂芳基)烷基酰胺到“纯”N-烷基酰胺的转变伴随着抗炎作用的显著降低甚至完全丧失，而镇痛活性仍然存在。
根据研究，N-烷基-4-甲基-2,2-二氧代-1H-2λ,1-苯并噻嗪-3-甲酰胺类化合物具有成为潜在抗炎和镇痛药的潜力。
