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

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.

Dependence of the dynamics of changes in the quality of life of patients with bacterial vaginosis on local levels of TNF-α and IL-1ß.

BACKGROUND AND AIM: Bacterial vaginosis is among serious health problem for women of reproductive age which influences on their local changes in inflammatory mediators and quality of life. The aim was to assess the dependence of the dynamics of changes in the quality of life of patients with bacterial vaginosis on local levels of TNF-α and IL-1ß. METHODS: In the prospective study 37 women aged 19-40 years with bacterial vaginosis were treated according to the Centers for Disease Control and Prevention. Patients received vaginal suppositories of clindamycin phosphate (100 mg) once daily for 3 days before bedtime. TNF-α, IL-1ß levels in vaginal secretions by means of ELISA test), as well as the quality of life according to the RAND 36-Item Health Survey 1.0 were studied as in control group (once - to determine the reference values) and in the dynamics (the 1st day - before treatment, on the 7th day - after treatment) in the main group. RESULTS: After the treatment microscopy of smears-imprints of vaginal secretions showed the complete absence of pathological microflora. The treatment was well tolerated by all patients. In the result there was proved the role of bacterial vaginosis in a violation of the quality of life of patients mainly due to the mental component of health, even after clinical and laboratory recovery. CONCLUSIONS: There was proved the relation of vaginal TNF-α and IL-1ß with physical and mental health in patients with bacterial vaginosis which can have a prognostic significance of the disease.