Imidazo[2,1-b]thiazole based indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor: Structure based design, synthesis, bio-evaluation and docking studies.

Indoleamine-2,3-dioxygenase 1 (IDO1) is an immunomodulatory enzyme known to catalyse the initial and rate limiting step of kynurenine pathway of l-tryptophan metabolism. IDO1 enzyme over expression plays a crucial role in progression of cancer, malaria, multiple sclerosis and other life-threatening diseases. Several efforts over the last two decades have been invested by the researchers for the discovery of different IDO1 inhibitors and the plasticity of the IDO1 enzyme ligand binding pocket provide ample opportunities to develop new heterocyclic scaffolds targeting this enzyme. In the present work, based on the X-ray crystal structure of human IDO1 coordinated with few ligands, we designed and synthesized new fused heterocyclic compounds and evaluated their potential human IDO1 inhibitory activity (compound 30 and 41 showed IC50 values of 23 and 13 µM, respectively). The identified HITs were observed to be non-toxic to HEK293 cells at 100 µM concentration. The observed activity of the synthesized compounds was correlated with the specific interactions of their structures at the enzyme pocket using docking studies. A detailed analysis of docking results of the synthesized analogues as well as selected known IDO1 inhibitors revealed that most of the inhibitors have some reasonable docking scores in at least two crystal structures and have similar orientation as that of co-crystal ligands.

Novel Vanillin-based hybrids inhibit quorum sensing and silences phenotypical expressions in Pseudomonas aeruginosa.

In this study, we report the chemical synthesis, computational analysis, and anti-virulent studies of five Vanillin-based hybrids employing phytochemicals. Vanillin (V) is known to have substantial anti-quorum sensing activity against the gram-negative pathogen Pseudomonas aeruginosa. Therefore, with the aim to further enhance the potency of Vanillin, it was chemically conjugated via a triazole (T) linker with five phytochemicals- Zingerone (Z), Eugenol (E), Guaiacol (G), Cinnamaldehyde (C), and Ferulic acid (F) to form the hybrids named as VTZ (1), VTE (2), VTG (3), VTC (4), and VTF (5), respectively. Molecular docking studies revealed the strong binding affinity of the designed hybrids with quorum-sensing receptors (LasR, Rh1R, and PqsR). The synthesized hybrids were also evaluated for anti-quorum sensing activities to examine the efficacy against P. aeruginosa bacterial strains PAO1. The hybrids VTE (2), VTG (3), and VTC (4) displayed improved anti-quorum activity relative to Vanillin. Furthermore, the attenuation of virulence factors of P. aeruginosa (Las-A protease, Las-B elastase, pyocyanin pigmentation, and motility) in the presence of VTE (2), VTG (3), and VTC (4) further authenticated the anti-virulent activity of the hybrids. The new design strategy of the phytochemical-phytochemical scaffolds and their biological evaluation provides a proof of concept for the simultaneous perturbation of well-established anti-virulent targets. This appears to be highly promising and effective strategy to ameliorate the enigma of antimicrobial resistance.