Synthesis And Antimicrobial Activities Of Novel Sulfanilamide-derived 1,2,3-triazoles

Sulfonamides as antibacterial agents were extensively used in medicinal field. With the further extension of sulfonamide compounds as drugs, the researches in sulfanilamide-based derivatives have become more and more active in antifungal, antiviral, antitumor aspects and so on. 1,2,3-Triazole derivatives are an important class of nitrogen-containing aromatic heterocycles, and have attracted a great deal of interest due to their diverse biological activities, along with the development of'click chemistry'for their easy synthesis. This thesis based on the current situation of sulfonamides as antibacterial and antifungal agents, designed and synthesized a series of novel sulfanilamide-derived 1.2,3-triazoles. The structures and antimicrobial activities of synthesized compounds were characterized, and all compounds were investigated in vitro for their antibacterial and antifungal activities and preliminary structure-activity relationships were also discussed. The main contents are summarized as follows:Acetyl-protected propargyl sulfonamide 40 was synthesized through multi-step reactions including chloro-sulfonation, ammoniation and propargylation starting from commercially available acetanilide, and then treated with diluted hydrochloric acid to yield the deprotected propargyl sulfonamide 41. The 1,3-cycloaddition of compound 41 with a series of azides via'click reaction' produced novel sulfanilamide 1,2,3-triazoles including alkyl mono-1,2,3-triazole 42a-f, benzyl or substituted benzyl mono-1,2,3-triazole 43a-i. Bis-propargyl sulfanilamide 46 with a series of azides via 'click synthesis'afforded benzyl or substituted benzyl bis-1,2,3-triazole 47a-h, and further deprotected by aqueous sodium hydroxide to give free sulfanilamide bis-1,2,3-triazole 48a-h.The sulfanilamide azide derivative 49 reacted with a variety of propargyl azoles via 1,3-cycloaddition to produce a new series of 1,2,3-triazole-bridged sulfanilamide diverse azoles 51a-h.All new compounds were confirmed by 1H NMR,13C NMR, IR and MS spectra, and some compounds were furher analyzed by HRMS spectra and elemental analyses. The antimicrobial activities indicated that the synthesized sulfanilamide triazole derivatives exhibited antibacterial and antifungal activities, to some extent, against all the tested stains in vitro, and some title compounds showed moderate inhibitory efficacy. Dodecyl sulfanilamide mono-1,2,3-triazole 42e and 2,4-diflurorobenzyl derivative 43i showed stronger antibacterial activities against P. aeruginosa and S. dysenteriae with MIC values ranging from 16 to 32μg·mL-than other sulfanilamide mono-1,2,3-triazole, and these compounds were worthy of further development.All the synthesized sulfanilamide bis-1,2,3-triazoles exhibited poor antimicrobial activities, except that 2,4-dichlorobenzyl derivative 48d and 2,4-diflurorobenzyl one 48e showed better antibacterial efficiency against all tested strains. Among these synthesized sulfanilamide bis-triazoles, compound 48d gave best anti-P. aeruginosa efficacy with an MIC value of 128 ug-mL-1.Among 1,2,3-triazole-bridged sulfanilamide azoles,1,2,4-triazole derivative 51a gave the best antifungal activity, while 4-nitroimidazole-based compound 51e showed the strongest antibacterial efficacy.The structure-activity relationships showed that the incorporation of 1,2,3-triazole ring is helpful to improve the antibacterial and antifungal activities. Alkyl chain and benzyl or substituted benzyl groups could efficiently effect on physicochemical properties and thus improve biological activity. The azole ring should be greatly helpful for antimicrobial activity. Specially,1,2,4-triazole moiety is conducive to antifungal activity, while 4-nitroimidazole moiety seems to be favourable for antibacterial efficacy. The introduction of diphenyl piperazine is beneficial to improve the inhibition activity of the sulfanilamide precurosor.In this work, sixty-eight compouds were successfully synthesized. Among these prepared compounds, forty-two of them were new including fifteen sulfanilamide-derived mono-1,2,3-triazoles and one intermediate, eight acetyl-protected sulfanilamide bis-1,2,3-triazoles and two intermediates, eight benzyl or substituted benzyl bis-1,2,3-triazoles, eight 1,2,3-triazole-bridged sulfanilamide azoles.