Abstract: Triazolo[3,4-b][1,3,4]thiadiazole core is the condensed thia/aza-containing bicyclic system combining 1,2,4-triazole and 1,3,4-thiadiazole rings, which represent an interesting class of heterocyclic compounds. Thus, functionalized derivatives incorporating triazolo[3,4-b]thiadiazole are of essential significance and particular interest for both the pharmaceutical and agrochemical industries due to their wide spectrum of biological properties. Considering the wide synthetic possibilities as well as a diverse range of pharmacological activities, triazolo[3,4-b][1,3,4]thiadiazoles have received considerable attention from the scientific community as a prospective structural scaffold for rational drug-like molecules build-up. In this review, we have attempted to summarize the literature data about the main synthetic approaches for obtaining triazolo[3,4-b][1,3,4]thiadiazole-based molecules as promising objects for modern bioorganic and medicinal chemistry.
Keywords: triazolo[3,4-b][1,3,4]thiadiazoles; fused heterocycles; synthesis; chemical modification; multistep transformation; cyclocondensation; molecular hybridization.

Triazolo[3,4-b][1,3,4]thiadiazole molecules are found to be important tools in modern bioorganic and medicinal chemistry. This condensed system successfully combines two pharmacologically significant five-membered heterocycles – 1,2,4-triazole and 1,3,4-thiadiazole, which causes much more interest in the enhanced activity profile of its analogs than their parent separate constituents. It’s considered that the triazoles fused to thiadiazoles exhibit various therapeutically important properties, probably due to the existence of N-C-S fragments in their structures. In this review, we presented the summarized literature data about the diversity of pharmacological effects of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole based compounds as promising objects for the rational design of drug-like molecules.

Objective: A convenient and effective method for the obtaining of a 4-thiazolidinone ring is theт[2+3]-cyclocondensation reaction of S,N-binucleophiles with different equivalents of the dielectrophilic synthon [C2]2+. For this purpose, we achieved the synthesis of intermediate N1- methylidenethiosemicarbazones 3a-b starting from 2-amino/allylsulfanyl-5-ethyl-1,3,4- thiadiazoles 1-b via Vilsmeier-Haak formylation reaction following by condensation with thiosemicarbazide in acetic acid medium.
Methods: Organic Synthesis, NMR Spectroscopy, Elemental analysis, Pharmacological screening.
Results: The interaction of intermediate N1-methylidenethiosemicarbazones 3a-b with αhalocarboxylic (monochloroacetic, 2-bromopropionic, 2-bromobutanoic) acids or α-bromo-γbutyrolactone in acetic acid at the presence of sodium acetate was performed. As results, a series of targeted 2-hydrazino-4-thiazolidinones containing 6-phenylimidazo[2,1-b] [1,3,4] thiadiazole moiety 4a-b and their 5-alkyl substituted derivatives 5a-d and 6a-b were obtained. The structure of the synthesized compounds was confirmed by elemental analysis and NMR spectroscopy. The synthesized compounds 3a-b, 4a-b, 5a-d, and 6a-b were evaluated for their in vitro antitrypanosomal activity against Trypanosoma brucei gambiense (Feo strain).
Conclusion: The results of in vitro screening of antitrypanosomal activity against Trypanosoma brucei gambiense (TBG) allowed us to identify three highly active compounds 4b, 5b and 5c, whichбexhibited significant trypanocidal activity with a range of IC50 values of 3.7-4.4 µM and were comparable to the reference drug nifurtimox (IC50 = 4.4 µM). 

In the present work, we report an efficient synthesis and antioxidant activity evaluation of some 4-arylimino-thiazolidin-2-ones. The structures of target substances were confirmed through 1H and 13C NMR spectroscopy, mass spectrometry and elemental analysis. The antioxidant activity of the synthesized compounds was measured in vitro by the method of scavenging effect on 2,2- diphenyl-1-picrylhydrazyl (DPPH) radicals. Notably, antioxidant activity was identified for the first time among 4-arylimino-thiazolidin-2-ones.

A series of novel 1,3,4-thia(oxa)diazole substituted 2-(2,4-dioxothiazolidine-5-ylidene)-acetamides 3a-c, 4 and 5a-k have been synthesized following the acylation reaction of 2-amino-5-aryl-1,3,4-oxadiazoles, 5-amino-1,3,4-thiadiazole-2-thiol and it’s S-alkylated derivatives with 2-(2,4-dioxothiazolidine-5-ylidene)acetyl chloride in dioxane medium. The functionalization of compounds 3b, 3c, 5d and 5e was carried out on their N3 position under N-alkylation conditions with N-aryl-2-chloroacetamides in DMF/ethanol medium yielded the corresponding 2,4-dioxothiazolidine-3,5-diacetic acid diamides 6a-e and 7a-b. The structures of target compounds were confirmed by using 1H NMR spectroscopy and elemental analysis. The antioxidant activity evaluation in vitro of the synthesized compounds was performed by the method of scavenging effect on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals. As a result, the highly active compound 4, namely 2-(2,4-dioxothiazolidin-5-ylidene)-N-(5-mercapto-[1,3,4]thiadiazol-2-yl)acetamide was found to be the most efficient candidate among all compounds with a radical scavenging ability of 88.9%, which was comparable that for ascorbic acid (92.7%). The experimentally calculated IC50 value of 43.1 μM for compound 4 was lower than for ascorbic acid (50.5 μM).