Pyrrolidine, compounds bearing pyrrolidine-thiazol ring, preparation of some metal complexes, characterization, investigation of their bioactivity and ionization constants determination

In this doctoral thesis, pyrrolidine-thiazole derivatives containing pyrrolidine, thiazole, and indole ring systems, which are known to be biologically active moieties and platinum(II) and cobalt(III) complexes of some N-acylthiourea pyrrolinates derivatives were synthesized. In vitro antibacterial, antituberculosis, and antifungal activities of these synthesized molecules were investigated. Then, the acid ionization constants of some obtained N'-acylthiourea prolinates and thiazoles were determined. In the first step, pyrrolidine derivatives were synthesized via imine-azomethine-yilide-1,3-dipolar cycloadditions reactions of aldimines obtained from corresponding amino acid esters and aldehydes. Then functionalized bidentate N'-acylthiourea prolinates were synthesized in an atom economy manner by condensation of pyrrolidines and benzoylisothiocyanate. Pyrrolidine-thiazole derivatives, bearing different functional groups, were then synthesized via the sequential reaction of N'-acylthiourea prolinates with α-bromo ketones. In the second step, the stable, neutral, square plane, and tetracoordinated platinum (II) complexes were obtained by the reaction of the cyclic and bicyclic derivatives of some bidentate functional N'-acylthiourea prolinates with potassiumtetrachloroplatinate (K2PtCl4). In addition, potentially bioactive with six coordination cobalt(III) complexes were also synthesized by the reaction of some N'-acylthiourea prolinate derivative ligands with cobalt(II) acetate tetrahydrate. The structures of the synthesized novel molecules were elucidated and characterized by spectroscopic/analytical techniques such as 1H NMR, 13C NMR, MS, IR, HRMS/elemental analysis, and Single Crystal X-Ray studies. In the third step, the antibacterial, antifungal, and antituberculosis activities of the novel pyrrolidine, N'-acylthiourea prolinates, pyrrolidine-thiazole, platinum(II), and cobalt(III) complexes were tested. The antibacterial activities of the target compounds were compared with the reference drug ampicillin by screening against bacteria Staphylococcus aureus (ATCC 25925), Bacillus subtilis (ATCC 6633), Aeromonas hydrophila (ATCC 95080), Escherichia coli (ATCC 25923) and Acinetobacter baumanii (ATCC 02026). The antituberculosis (TB) activities of the novel compounds were compared with reference drugs ethambutol (EMB, Sigma E4630) and isoniazid (INH, Sigma I3377) against M. tuberculosis H37Rv strain. The antifungal activities of the compounds were investigated against standard strains of C. albicans (ATCC 14053), C. tropicalis (ATCC 1369), and C. glabrata (ATCC 15126) using fluconazole as a reference. In the fourth step, the acid ionization constants of some N'-acylthiourea prolinates and some pyrrolidine-thiazole derivative compounds, which are known as important parameters in drug discovery and development processes, were determined by the potentiometric titration method. The mL-pH graphs used to determine the ionization constants were obtained by the titrations of the prepared solutions at 2x10-4 M concentrations against 0.025 M NaOH base. Experimental studies were carried out in Acetonitrile:water (20:80 v/v) medium, with the addition of 0.03 mL of 0.025 M NaOH base at 25 ± 0.1 ºC. Acid ionization constants were calculated with by the HYPERQUAD computer program from mL-pH graphic data obtained from the results of potentiometric titrations.