Potential bacterial biofilm, MRSA, and DHFR inhibitors based on new morpholine-linked chromene-thiazole hybrids: One-pot synthesis and in silico study

We report herein the utility of the morpholine-linked benzaldehyde as a key building block in the preparation of two series of new chromene-thiazoles with potential bioactivities. In this regard, a one-pot protocol was developed involving the reaction of the prior aldehyde, 2-cyanothioacetamide and alpha-bromoketones in dioxane in the presence of triethylamine to give the target hybrids. Thiazole hybrids 9d and 9e , attached to two chromene units at thiazole-C2 and C4, and linked to methyl or methoxy groups, respectively, showed the best antibacterial activity. The previous hybrids exhibited MIC/MBC values of 3.9/7.8 and 1.7/3.5 mu M, respectively, against S. aureus, S. mutans and E. coli strains. In addition, the same hybrids gave MIC values of 7.7-32.0 mu M and MBC values of 15.5-64.1, mu M against MRSA ATCC:33,591 and ATCC:43,300 strains. Furthermore, 9d and 9e gave the best bacterial biofilm inhibitory activity against S. aureus, S. mutans and E. coli strains with IC50 values ranging from 3.9 to 4.6 mu M. Also, 9e and 9d displayed superior dihydrofolate reductase enzyme inhibitory activity with IC50 values of 0.122 and 0.131 mu M, respectively, compared to the standard sulfadiazine (IC50 value of 0.138 mu M). Molecular docking study was used to determine the binding energies of some new hybrids with the previous enzyme. Moreover, physicochemical, pharmacokinetic properties, and drug-likeness of some new hybrids were calculated using SwissADME. (C) 2021 Elsevier B.V. All rights reserved.