Suraj N. Mali, Sudhir Sawant, Hemchandra K. Chaudhari* and Mustapha C. Mandewale Pages 445 - 455 ( 11 )
Background: Thiadiazole not only acts as “hydrogen binding domain” and “two-electron donor system” but also as constrained pharmacophore.Methods: The maleate salt of 2-((2-hydroxy-3-((4-morpholino-1, 2,5-thiadiazol-3-yl) oxy) propyl) amino)- 2-methylpropan-1-ol (TML-Hydroxy)(4) has been synthesized. This methodology involves preparation of 4-morpholino-1, 2,5-thiadiazol-3-ol by hydroxylation of 4-(4-chloro-1, 2,5-thiadiazol-3-yl) morpholine followed by condensation with 2-(chloromethyl) oxirane to afford 4-(4-(oxiran-2-ylmethoxy)-1,2,5-thiadiazol- 3-yl) morpholine. Oxirane ring of this compound was opened by treating with 2-amino-2-methyl propan-1- ol to afford the target compound TML-Hydroxy. Structures of the synthesized compounds have been elucidated by NMR, MASS, FTIR spectroscopy. Results: The DSC study clearly showed that the compound 4-maleate salt is crystalline in nature. In vitro antibacterial inhibition and little potential for DNA cleavage of the compound 4 were explored. We extended our study to explore the inhibition mechanism by conducting molecular docking, ADMET and molecular dynamics analysis by using Schrödinger. The molecular docking for compound 4 showed better interactions with target 3IVX with docking score of -8.508 kcal/mol with respect to standard ciprofloxacin (docking score= -3.879 kcal/mol). TML-Hydroxy was obtained in silico as non-carcinogenic and non-AMES toxic with good percent human oral absorption profile (69.639%). TML-Hydroxy showed the moderate inhibition against Mycobacteria tuberculosis with MIC 25.00 μg/mL as well as moderate inhibition against S. aureus, Bacillus sps, K. Pneumoniae and E. coli species. Conclusion: In view of the importance of the 1,2,5-thiadiazole moiety involved, this study would pave the way for future development of more effective analogs for applications in medicinal field.
Heterocycle, tuberculosis, DNA cleavage, molecular docking, thiadiazole, antibacterial.
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga (E), Mumbai, Maharashtra, FDC Limited Research & Development Centre, Charkop, Kandivali West, Mumbai, Maharashtra, Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga (E), Mumbai, Maharashtra, FDC Limited Research & Development Centre, Charkop, Kandivali West, Mumbai, Maharashtra