ABSTRACT
In this study, a series of polysubstituted methyl 5,5-diphenyl-1-(thiazol-2-yl)pyrrolidine-2-carboxylate derivatives were designed and synthesized by the cyclization reaction of methyl 1-(benzoylcarbamothioyl)-5,5-diphenylpyrrolidine-2-carboxylates and 2-bromo-1-(4-substituted phenyl)ethanones in 70-96% yield. The starting pyrrolidine derivatives were synthesized via a 1,3-dipolar cycloaddition reaction in 83-88% yield. The stereochemistry of one of these methyl 5,5-diphenyl-1-(thiazol-2-yl)pyrrolidine-2-carboxylate derivatives was characterized by a single crystal X-ray diffraction study and the acid dissociation constants of these compounds were determined. An antimicrobial screening was performed against different bacterial and fungal strains and against the M. tuberculosis H37Rv strain. Interesting antibacterial activity was observed for two compounds against the A. baumannii strain with MIC values of 31.25⯵g/mL (Ampicillin: 125⯵g/mL) and against the M. tuberculosis H37Rv strain with MIC values of 0.98-1.96⯵g/mL (Isoniazid: 0.98⯵g/mL, Ethambutol: 1.96⯵g/mL). Therefore, these structures can be considered as good starting points for the development of new powerful antimycobacterial agents.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Bacteria/drug effects , Fungi/drug effects , Pyrrolidines/pharmacology , Thiazoles/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Cycloaddition Reaction , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
The acid dissociation constants of potential bioactive fused ring thiohydantoin-pyrrolidine compounds were determined by potentiometric titration in 20% (v/v) ethanol-water mixed at 25 ± 0.1°C, at an ionic background of 0.1 mol/L of NaCl using the HYPERQUAD computer program. Proton affinities of potential donor atoms of the ligands were calculated by AM1 and PM3 semiempiric methods. We found, potentiometrically, three different acid dissociation constants for 1a-f. We suggest that these acid dissociation constants are related to the carboxyl, enol, and amino groups.
