Advances in the Synthesis of Triazolothiadiazoles and their Biological Applications
Ola Mohamed
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
Nesreen Saied Haiba
Department of Physics and Chemistry, Faculty of Education, Alexandria University, Egypt.
Mohamed Teleb
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
Hayam M.A. Ashour
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt and Department of Medicinal Chemistry, Faculty of Pharmacy, Galala University, New Galala 43713, Egypt.
Sherry N. Nasralla
Pharmacy Program, Allied Health Department, College of Health Sciences, University of Bahrain, P.O. Box 32038, Bahrain.
Sherine N. Khattab
Chemistry Department, Faculty of Science, Alexandria University, Alexandria, 21321, Egypt.
Adnan A. Bekhit *
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt and Pharmacy Program, Allied Health Department, College of Health Sciences, University of Bahrain, P.O. Box 32038, Bahrain.
*Author to whom correspondence should be addressed.
Abstract
Triazolothiadiazoles are fused nitrogen- and sulfur-containing heterocycles with versatile synthetic chemistry and a broad range of reported biological activities. This narrative review examines representative strategies for the synthesis of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives and critically summarises structure–activity relationships across anticancer, antimicrobial, acetylcholinesterase-inhibitory, anti-inflammatory, analgesic, anticonvulsant, and emerging urease-inhibitory applications. The literature was updated through 27 September 2026 by targeted searches of PubMed, journal and publisher platforms, and DOI-based bibliographic records, with peer-reviewed primary studies prioritised for quantitative biological data. Common synthetic routes proceed through 4-amino-5-substituted-4H-1,2,4-triazole-3-thiols followed by cyclocondensation with carboxylic acids, aldehydes, or related electrophiles; microwave-assisted and visible-light-mediated variants have also been reported. Across individual series, halogen, alkoxy, nitro, aryl, glycosyl, and lipophilic substituents can alter activity, but these effects are assay- and scaffold-dependent rather than universally predictive. Representative studies have reported micromolar antiproliferative and acetylcholinesterase-inhibitory activity, antimicrobial effects at low microgram-per-milliliter concentrations, preclinical anti-inflammatory and anticonvulsant activity, and submicromolar-to-low-micromolar urease inhibition. Most evidence remains preclinical and heterogeneous, with limited pharmacokinetic, selectivity, and repeated-dose toxicity data. The scaffold therefore remains a useful platform for medicinal and bioactive chemistry, while standardised comparative assays, target validation, and in vivo translational studies are required to establish therapeutic relevance.
Keywords: Triazolothiadiazole, heterocyclic synthesis, fused triazoles, structure–activity relationship, anticancer activity, antimicrobial activity, acetylcholinesterase inhibition, anti-inflammatory activity, anticonvulsant activity, urease inhibition