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[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 Publisher Pubmed



Khalili Ghomi M1, 2 ; Noori M1 ; Nazari Montazer M1 ; Zomorodian K3 ; Dastyafteh N4 ; Yazdanpanah S3 ; Sayahi MH5 ; Javanshir S4 ; Nouri A3 ; Asadi M6 ; Badali H7 ; Larijani B1 ; Irajie C8 ; Iraji A2, 9 Show All Authors
Authors
  1. Khalili Ghomi M1, 2
  2. Noori M1
  3. Nazari Montazer M1
  4. Zomorodian K3
  5. Dastyafteh N4
  6. Yazdanpanah S3
  7. Sayahi MH5
  8. Javanshir S4
  9. Nouri A3
  10. Asadi M6
  11. Badali H7
  12. Larijani B1
  13. Irajie C8
  14. Iraji A2, 9
  15. Mahdavi M1

Source: Scientific Reports Published:2023


Abstract

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 IC50 values of 0.87 ± 0.09 to 8.32 ± 1.21 µM as compared with thiourea as the positive control (IC50 = 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 significant antifungal activities with MIC values of 1, 2, and 0.5 µg/mL compared with fluconazole with MIC = 2 µg/mL. Synthesized analogs also exhibited potent urease inhibitory activities against C. neoformans (IC50 = 83.7–118.7 µg/mL) and P. mirabilis (IC50 = 74.5–113.7 µg/mL), confirming their urease inhibitory potential. The results demonstrated that the designed scaffold could be considered a suitable pharmacophore to develop potent urease inhibitors. © 2023, The Author(s).
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