Computational Design of Azine-Linked Hybrids of 2-Indolinone-Thiazolodine Scaffold as Novel and Promising Quorum Sensing Inhibitors

Abstract

Microbial multidrug resistance is becoming a global menace to humanity, and finding alternative approaches to combat these “superbugs” is critical. Targeting quorum sensing (QS), which is essential for bacterial biofilm formation and virulence factors production, represents a viable alternative strategy for combating a variety of diseases. Accordingly, the current work reports potential QS inhibitors (QSIs), which could target the transcriptional regulator protein CviR in the model QS bacterium Chromobacterium violaceum. A set of novel hybrids 4(a–k) were synthesized using the virtual screening results of structurally based hybrids of the 2-indolinone-thiazolidine scaffold on the CviR active pocket residues. The ability of these hybrids to inhibit the QS system was tested against C. violaceum, and two molecules (4h and 4i) revealed promising antivirulence activity. Biofilm formation and motility were both impaired in the treated bacterial cells. Moreover, the molecular docking of these two compounds was comparable with that of chlorolactone (CL), a native inhibitor of the C. violaceum CviR. The global chemical descriptors were calculated for compounds 4h and 4i and found to be more reactive than the native inhibitor, CL. Furthermore, the in silico ADME prediction profiles of these two lead compounds, 4h and 4i, showed good ADME profiles.