Some pharmacological properties of pyrrolidine derived compounds: İn vitro and İn vivo studies

The novel drug research and development (R&D) studies are important and crucial due to the resistance to some drugs used in treatment, undesirable side effects and limited bioavailability of them in therapies. In this thesis, some novel potentially bioactive hybrid pyrrolidine derivative molecules containing one or more of indole, thiourea, vinylsulfone pharmacophore groups were synthesised and their various pharmacological properties were investigated by in vitro, in vivo and in silico studies. Thus, the novel substituted hybrid pyrrolidines compounds were prepared from imines, derived from corresponding amino acids, via imine azomethine yilide 1,3-dipolar cycloaddition reactions. The novel hybrid aminocarbothiol-pyrrolidine benzoylisothiothionate derivative were than obtained by condensation of pyrrolidine with benzoylisothiothionate.The structures of novel molecules were determined using analytical techniques such as 1H-NMR, 13C-NMR, HRMS, FT-IR and X-Ray. The synthesized new molecules were then tested for their anti(myco)bacterial by using resazurin microtiter method (REMA), antibacterial using resazurin microplate method, antifungal using liquid microdilution method, anticancer activity using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test, antidepressant activity using forced swimming test, antioxidant capacity using 2,2′-diphenyl-1-picryl hydrazyl hydrazyl hydrate (DPPH) test, antioxidant activity using superoxide dismutase (SOD1) enzyme level and antiinflammatory activity using cyclooxygenase-2 (COX-2) enzyme level were investigated using ELISA test. The binding energies and some pharmacokinetic properties of prepared novel hybrid pyrrolidine derivatives were investigated using in silico molecular docking studies against COX-2 enzyme, and absorption-distribution-metabolism-elimination-toxicity (ADMET) studies. The new pyrrolidine derivative hybride molecule bearing divinylsulfone pharmacophore group 6a, shown better pharmacological activities when comparing to other obtained pyrrolidine and aminocarbotiol-pyrrolidine (6b, 8) hybride molecules.