Novel Pyrimidine Trizoles:Design, Synthesis And Their Antimicrobial Evaluation

Pyrimidine is a six-membered aromatic heterocyle containing two nitrogen atoms, it is extensively present in natural and synthetic drugs in which pyrimidine moiety plays important roles in exerting various biological activities. Thus it has been paid special attention in the development of new drugs. Especially as antibacterial and antifungal aspects such as Voriconazole, Sulfadiazinmu argenteum, and Fluorocytosine are widely used in clinic to treat infective diseases. In recent years,1,2,4-triazole nucleus as pharmacophore is frequently employed in drug design, and many researches were directed towards its derivatives and considerable outstanding achievements have been obtained in antibacterial and antifungal aspects. In this thesis, based on the current situation in the researches of pyrimidine compounds, a series of novel pyrimidine triazoles were designed and synthesized. These novel compounds were evaluated for their antibacterial and antifungal activity as well as their interaction with calf thymus DNA, Human Serum Albumin and metal ions. The preliminary structure-activity relationships were also discussed. The main work was summarized as follows:(1) Preparation of α-triazolyl chalcones:a-Triazolyl chalcones32a-j,33a-c and34a-c were synthesized via a convenient and efficient "one-pot" procedure from various substituted benzaldehydes and triazolyl ethanones31a—d which were obtained by Friedel-Crafts acylation and then N-alkylation of1,2,4-triazole starting from commercial available substituted benzenes.(2) Preparation of novel pyrimidine triazole compounds:A series of pyrimidine triazole compounds37a-b and38a-j were synthesized by a convenient procedure, starting from a-triazolyl chalcones32a-j, guanidine hydrochloride, urea and thiourea, in the presence of sodium methoxide in methanol to generate the intermediate compounds35a-b and36a-j, further reaction with cuprous chloride as dehydrogenated catalyst to generate target compounds. (3) The preparative condition of pyrimidine triazoles was explored, and the suitable reaction condition was found.(4) The newly synthesized compounds were characterized by1H NMR,13C NMR,1R, MS and HRMS spectra. The single crystals of intermediate compounds32a,32d,32e,32f,32g,33a,33c and target compound38f were obtained by solvent evaporation method at room temperature. Their crystal structures were determined by Brucker SMART diffractometer, which confirmed the spatial structures of these title compounds.(5) The in vitro antibacterial and antifungal assays indicated that most synthesized compounds could significantly inhibit the growth of all the tested microorganisms and some of them displayed equipotent or superior activities to the current clinical drugs. Notably,4-chloro-substituted compound38f gave better inhibition against B. subtilis (MIC=16μg/mL) and MRS A (MIC=8μg/mL) than reference drug Chloromycin. Moreover, methyl derivative38b exhibited comparable inhibitory behaviors against B. proteus (MIC=32μg/mL), E. coli (MIC=16μg/mL) to the reference drug Chloromycin.(6) The preliminary structure-activity relationships showed that the introduction of halogen groups enhanced the antimicrobial potencies of pyrimidine triazoles to some extent. While the incorporation of hydroxyl and thiol groups were not conductive to the biological activities.(7) The specific interaction of compound38f with calf thymus DNA displayed that compound38f could intercalate into DNA to form38f-DNA complex which might further block DNA replication to exert its powerful antibacterial and antifungal activities. Binding investigations with HSA revealed that HSA could generate fluorescent quenching by38f as a result of the formation of ground-state38f-HSA complex, and the calculated parameters suggested that the binding process should be spontaneous. Hydrophobic interactions and hydrogen bonds played an important role in the binding of compound38f to HSA, while electrostatic interactions might be also involved in the binding process.(8) Competitive interactions between38f and metal ions to HSA suggested that only Al3+ion among all the test ions in38f-HSA system could increase the concentration of free compound38f, shorten its storage time and half-life in the blood, and thus improve the maximum antimicrobial efficacies. Forty eight compounds were successfully synthesized in this thesis. Forty compounds were new, including sixteen a-triazolyl chalcones, one thiol dihydropyrimidine, one hydroxyl pyrimidine, ten amino dihydropyrimidines, one thiol pyrimidine, one hydroxyl pyrimidine and ten amino pyrimidines.