Synthesis, Crystal Structure, and Biological Activity of 4-Methyl-1,2,3-thiadiazole-Containing 1,2,4-Triazolo[3,4-b][1,3,4]thiadiazoles

Heterocyclic compounds play an important role as the main sources of lead molecules of agrochemicals. Synthesis and biological activity of thiadiazole-containing 1,2,4-triazolo[3,4-b][1,3,4]-thiadiazoles were seldom reported. To find novel lead compounds with various biological activities, a series of 6-substituted-3-(4-methyl-1,2,3-thiadiazolyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadizoles were rationally designed and synthesized according to the principle of combinations of bioactive substructures by the condensation of 3-(4-methyl-1,2,3-thiadiazolyl)-4-amino-1,2,4-triazole-5-thione with various carboxylic acids and phosphorus oxychloride. All newly synthesized compounds were identified by proton nuclear magnetic resonance (H-1 NMR), infrared spectroscopy (IR), electroionization mass spectrometry (EI/MS), and elementary analysis, The crystal structure of 3-(4-methyl-1,2,3-thiadiazolyl)-6-(4-methylphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadizole was determined by X-ray diffraction crystallography. In this crystal, two intermolecular hydrogen bonds (N2 center dot center dot center dot H-C12 and N3 center dot center dot center dot H-C13), a weak intermolecular interaction (S center dot center dot center dot S), and the weak p pi-p pi intermolecular interaction were observed. Fungicide screening indicated that all of the target compounds showed certain extent of growth inhibition against fungi tested. 3-(4-methyl-1,2,3-thiadiazolyl)-6-n-propyl[1,2,4]triazolo[3,4-b][1,3,4]thiadizole and 3-(4-methyl-1,2,3-thiadiazolyl)-6-trichloromethyl[1,2,4]triazolo[3,4-b][1,3,4]thiadizole were found to have potential wide spectrum of fungicide activity. The median effective concentrations (EC50) detected for 3-(4-methyl-1,2,3-thiadiazolyl)-6-trichloromethyl[ 1, 2,4] triazolo[3,4-b] [ 1, 3,4]thiadizole to six fungi were from 7.28 mu mol/L against Pellicularia sasakii (Shirai) to 42.49 mu mol/L against Altemaria solani. The results indicated that thiadiazole-containing 1,2,4-triazolo[3,4-b][1,3,4]-thiadiazoles were potential fungicide lead compounds.