1 Vol.:(0123456789) Scientifc Reports | (2023) 13:10136 | https://doi.org/10.1038/s41598-023-37203-z www.nature.com/scientificreports [1,2,4]triazolo[3,4‑b][1,3,4] thiadiazole derivatives as new therapeutic candidates against urease positive microorganisms: design, synthesis, pharmacological evaluations, and in silico studies Minoo Khalili Ghomi 1,2 , Milad Noori 1 , Mohammad Nazari Montazer 1 , Kamiar Zomorodian 3 , Navid Dastyafteh 4 , Somayeh Yazdanpanah 3 , Mohammad Hosein Sayahi 5 , Shahrzad Javanshir 4 , Abbas Nouri 3 , Mehdi Asadi 6 , Hamid Badali 7 , Bagher Larijani 1 , Cambyz Irajie 8 , Aida Iraji 2,9* & Mohammad Mahdavi 1* Regarding the important role of the urease enzyme as a virulence factor in urease‑positive microorganisms in this study, new series of [1,2,4]triazolo[3,4‑b][1,3,4]thiadiazole derivatives were designed and synthesized. All compounds evaluated against urease enzyme exhibiting IC 50 values of 0.87 ± 0.09 to 8.32 ± 1.21 µM as compared with thiourea as the positive control (IC 50 = 22.54 ± 2.34 µM). The kinetic evaluations of 6a as the most potent derivative recorded a competitive type of inhibition. Molecular dynamic simulations of the 6a derivative were also conducted, showing that 6a occupied the active site with closed state. Antimicrobial activities of all derivatives were performed, and 6f (R = 3‑Cl), 6g (R = 4‑Cl), and 6h (R = 3,4‑diCl) analogs demonstrated signifcant antifungal activities with MIC values of 1, 2, and 0.5 µg/mL compared with fuconazole with MIC = 2 µg/mL. Synthesized analogs also exhibited potent urease inhibitory activities against C. neoformans (IC 50 = 83.7–118.7 µg/ mL) and P. mirabilis (IC 50 = 74.5–113.7 µg/mL), confrming their urease inhibitory potential. The results demonstrated that the designed scafold could be considered a suitable pharmacophore to develop potent urease inhibitors. Urease (EC 3.5.1.5) is the frst known nickel-containing enzyme found in a wide variety of plants, algae, fungi, and bacteria that catalyzes the hydrolysis of urea to carbamic acids which are further hydrolysis to ammonia and carbon dioxide 1,2 . Urease is known as a virulence factor found in various pathogenic microorganisms in which OPEN 1 Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran. 2 Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. 3 Department of Medical Mycology and Parasitology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran. 4 Pharmaceutical and Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran 16846-13114, Iran. 5 Department of Chemistry, Payame Noor University (PNU), P.O. Box 19395-3697, Tehran, Iran. 6 Department of Medicinal Chemistry, School of Pharmacy-International Campus, Iran University of Medical Science, Tehran, Iran. 7 Department of Molecular Microbiology & Immunology, and South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX, USA. 8 Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran. 9 Central Research Laboratory, Shiraz University of Medical Sciences, Shiraz, Iran. * email: iraji@sums.ac.ir; aida.iraji@gmail.com; momahdavi@ sina.tums.ac.ir