Novel Triazolothiadiazole and Triazolothiadiazine Derivatives Containing Pyridine Moiety: Design, Synthesis, Bactericidal and Fungicidal Activities

Background: One of the important chemical agents in designing of anti-convulsant, antiatherosclerotic and anti-cancer drugs are pyridine derivatives. Alkyl and aryl derivatives of cyanopyridones show antimicrobial, antihypertensive, anti-inflammatory, analgesic, antipyretic properties as well as 1KK-b inhibitor properties. Methods: N-acyclic nucleosides 2-5 were synthesized by the reaction of the sodium salt of (4- chlorophenyl)-2-oxo-6-(thien-2-yl)-1,2-dihydroyridine-3-carbinitrile (1) with the halo derivatives: 2- chloroethanol, chloroacetaldehyde dimethylacetal, 2-chloroethyl methyl ether, and 2-(2- chloroethoxy)ethanol, respectively. On the other hand, the reaction of compound 1 with ethyl bromoacetate gave ethyl {2-((4-(4-Chlorophenyl)-3-cyano-6-(thien-2-yl)pyridin-2-yl)oxy)} acetic acid ester (6). Then, compound 6 reacted with thiocarbohydrazide or ethanolic sodium hydroxide solution producing 4-amino-5-thioxotriazolo derivative 7 or the free acid 8, respectively. Moreover, the reaction of compound 8 with thiosemicarbazide in the presence of phosphorus oxychloride gave the 5- aminothiadiazolyl derivative 9, which in turn gave the 5-oxothiadiazolyl derivative 10 upon nitrozation. Furthermore, compound 7 gave products 11, 13-19 when reacted with 4-chlorobenzaldehyde, isothiocyanate, benzoyl chloride, acetic anhydride, triethylorthoformate, carbon disulfide, , phenacyl bromide, bromoacetic acid, respectively. Finally, all the synthesized compounds were evaluated for their antibacterial Gram (+) and Gram (-) and anti-fungal activities. Results: Three compounds 2, 11 and 17 have high activity against pathogenic bacterial strains and gave inhibition zones ranged between 25 and 38 mm. Moreover, compounds 9, 10, 11, 12 and 18 showed auspicious anti-fungal activity. The MIC of the produced derivatives was calculated and the results indicated that some compounds had bioactivity up to 10 μg/ml. Conclusion: The new synthesized triazolothiadiazole and triazolothiadiazine derivatives containing pyridine moiety showed good bactericidal and fungicidal activities.