Design And Synthesis Of Novel Thio-triazoles And Evaluation For Their Antibacterial And Antifungal Activities

Triazole compounds represent an important nitrogen containing heterocycles and exert wide application in pharmaceutical field. Recently, the modification of triazole ring to design and synthesize novel structural bioactive molecules has aroused great attention and was widely used in antimicrobial aspects such as antibacterial, antifungal and antitubercular ones, etc. Based on the current investigation and development in thio-triazole derivatives, herein a series of new thio-triazole derivatives were designed and synthesized. The structures of all the new compounds were characterized by modern spectra. Their antibacterial and antifungal efficacies were evaluated and the preliminary structure-relationships were also investigated. The main contents were summarized as follows:1. Synthesis:100 thio-derivatives were prepared and sixty four compounds were new, including forty four halobenzyl thio-triazole derivatives, twenty naphthalimide thio-triazole compounds.(a) The new halobenzyl triazole-thiol 56 was synthesized starting from substituted benzyl halide and thiosemicarbazide via cyclization. Further N-alkylation and S-etherification with diverse substituted benzyl and haloalkyl halides produced the triazole thioethers 57 and 59 and thiones 58 and 60. The thioether bis-triazoles 61a-f and thione bis-triazoles 62a-f were prepared through the substitution of thio-triazole bromides with 1,2,4-triazole. Subsequently, the quaternization of triazole-thione 62b with various alkyl and halobenzyl halides as well as coumarin and carbazole bromides respectively afforded the bis-triazoliums 63-65.(b) The naphthalimide bromides 68a-e were synthesized using 6-bromobenzo[de] isochromene-1,3-dione as starting material via ammonification and substituted reactions, and the subsequent S-etherification and N-alkylation produced naphthalimide triazoles 70a-e, imidazoles 71a-e, thioethers 72a-c and thiones 73a-c. The following quaternization of azoles with diverse substituted benzyl and alkyl halides produced the corresponding azoliums 74-76. Moreover, the naphthalimide and its triazole derivative 70b respectively reacted with triazole-thiols to give naphthalimide thio-triazoles 69a-c and bis-triazoles 77a-c. Bis-triazoliums 78a-c were also prepared.2. All the new compounds were characterized by’H NMR, IR, MS and/or HRMS spectra, and some compounds were confirmed by 13C NMR and X-Ray diffraction.3. The in vitro antimicrobial evaluation manifested that all title compounds exhibited efficient antimicrobial activities to some extent and some compounds displayed efficient bioactivities, especially eighteen target compounds with satisfactory amtimicrobial activities were found (MIC< 32μg/mL).(a) Some efficient antibacterial compounds were obtained in the antimicrobial evaluation. The hexyl bis-triazolium 63a displayed satisfactory antimicrobial efficiencies, especially against S. aureus (MIC=2μg/mL), E. coli (MIC=1μg/mL) and P. aeruginosa (MIC=4μg/mL) which were comparable to the reference drugs Chloromycin and Norfloxacin. Meanwhile, the octyl triazolium 63b was more effective toward E. typhosa and P. aeruginosa than the reference drug Chloromycin with MIC values below 8μg/mL. Naphthalimide bis-triazolium compound 78b gave equipotent anti-MRSA, M. luteus and P. aeruginosa activities to Orbifloxacin with MIC values of 1μg/mL, while it was also sensitive to E. coli and B. typhi at low concentration of 2μg/mL which were more effective than Chloromycin.(b) Some compounds were also sensitive to the tested fungi. Compound 63a exerted low MIC value of 2μg/mL to C. albicans, meanwhile compounds 76a,78a and 78b exhibited equipotent anti-C. albicans competence to reference drug Fluconazole with MIC values of 1μg/mL and compound 78c was 2-fold more potent than the reference drug against C. mycoderma.(c) The pH and ClogP values remarkably affected the antimicrobial efficiencies. The results demonstrated that neutral to weak basic conditions (pH=7.0-7.5) which was similar to the pH in vivo and the low ClogP values seemed to be favorable for antimicrobial competence.4. Structure-activity relationship indicated that the introduction of thio-triazole moiety could improve the antimicrobial efficacy of the title compounds. The thiones were more favorable for the bioactivities than the thioethers. The introduction of positive azoliums could significantly increase the biological efficiencies and broaden the antimicrobial spectrum of target molecules. The linkers and halobenzyl moieties exerted remarkable effect to the antimicrobial activities. The incorporation of thio-triazole group into naphthalimide system might lead to improvement of antimicrobial competence. 5. The binding properties of high bioactive naphthalimide thio-triazole molecule 78b with BSA was investigated by fluorometric method. It was observed that the compound 78b could bind with BSA molecules via electrostatic interactions. This combination was favorable for the storage and transportation of the tested compound in the blood, thus promoting its diffusion in biological organism and improving the antimicrobial activities. Consequently, naphthalimide triazole 78b was worthy to be further investigated as potential antimicrobial drugs. The binding properties of the thio-triazole compounds 72c and 78b, naphthalimide carbazole 49b, and anthryl-bisnaphthalimide 83 with different cations were examed by UV-Vis spectroscopic method. Naphthalimide thio-triazole compound 72c could interact with Fe(Ⅱ) ion. Its good antifungal activity was probably due to its combination with protoheme Fe(Ⅱ) ion of P450 monooxygenase. Compound 78b also exerted good Fe(Ⅱ) ion complexation while it gave weak antifungal activity which was possibly assigned to its weak dissolubility in water. Moreover, compound 72c could also coordinate with Cu(Ⅱ) ion efficiently and was of much potential to be used as probes of Cu(Ⅱ) ion and cuprein.