Synthesis, characterization and anti-fungal potential evaluation of 1, 4 thiazine derivatives by Mannich bases

Abstract

Plan: The present research work is aimed to synthesize newer, less toxic and more effective Mannich bases of 1, 4 thiazine derivatives and further compare their antifungal activities. Preface: Microbial infections are becoming the most important issue for global health and economy. Among these fungal infections are the major problem these days. The morbidity and mortality of invasive fungal infections are unacceptably high. It is an urgent need for the development of new antifungal agents to treat these life-threatening invasive infections. Methodology: Mannich base was synthesized by using o-amino thiophenol with maleic anhydride. Further, four derivatives of Mannich bases were synthesized from 3-oxo-3, 4-dihydro-2H-1, 4-benzothiazin-2-yl) acetic acid with sulpha drugs, ethanol, and formaldehyde. Then synthesized Mannich bases were docked against Dihydrofolate reductase complexed with NADPH and 6- methyl-5- [3-methyl-3-(3,4,5-trimethoxyphenyl) but-1-yn-1-yl]pyrimidine-2,4-diamine (UCP115A)using Argus Lab software. On this basis, we selected 3QLS as a biological target for docking study of synthesized compound. Outcome: The structures of the synthesized compounds were confirmed by UV, IR and Mass Spectroscopic studies. All the newly synthesized derivatives were screened for antifungal activity against Candida albicans NCIM 3100 and Aspergillus niger NCIM 596 by agar diffusion method (Kirby- Bauer method) using fluconazole (10µg/disc) as the standard and dimethyl sulphoxide as the vehicle. The docking results indicate the Mannich bases of 1, 4-thiazines (ligand binding energy varies from -8.9046kcal/mol to -12,0457kcal/mol) shows considerable antifungal activity against Candida albicans. Out of the four derivatives, E4 (Sulfamethoxazole substituted 1, 4- thiazine) possess the best ligand pose energy (-12.0414 kcal/mol) and two hydrogen bond. Among these synthesized compounds, compound E4([4({[4-(N-(5-methyl-3-isoxazolyl) amino sulfonyl) phenyl] amino} methyl)-3-oxo-3,4-dihydro-2H1,4-benzothiazin-2yl] acetic acid) showed highest antifungal activity due to the presence of 1,4- thiazine with sulfamethoxazole substitution.