No abstract

With an alarming increase in the number of cancer patients and a variety of tumors, it is high time for intensive investigation on more efficient and potent anti-tumor agents. Though numerous agents have enriched the literature, still there exist challenges, with the availability of different targets and possible cross-reactivity. Herein we have chosen the phosphoinositide 3-kinase (PI3K) as the target of interest and investigated the potential of pyrido fused imidazo[4,5-c]quinoline derivatives to bind strongly to the active site, thereby inhibiting the progression of various types of tumors. The AutoDock, Glide and the Prime-MM/GBSA analysis are used to execute the molecular docking investigation and validation for the designed compounds. The anti-tumor property evaluations were carried out by using PASS algorithm. Based on the GLIDE score, the binding affinity of the designed molecules towards the target PI3K was evaluated. The energetics associated with static interactions revealed 1j as the most potential candidate and the dynamic investigations including RMSD, RMSF, Rg, SASA and hydrogen bonding also supported the same through relative stabilization induced through ligand interactions. Subsequently, the binding free energy of the Wortmannin and 1j complex calculated using MM-PBSA analysis. Further evaluations with PASS prediction algorithm also supported the above results. The studies reveal that there is evidence for considering appropriate pyrido fused imidazo[4,5-c]quinoline compounds as potential anti-tumor agents.

Tuberculosis is one of the most life‐threatening acute infectious diseases diagnosed in humans. In the present investigation, a series of 16 new disubstituted 1,3‐thiazetidines derivatives is designed, and investigated via various in silico methods for their potential as anti‐tubercular agent by evaluating their ability to block the active site of PrpR transcription factor protein of Mycobacterium tuberculosis. The efficacy of the molecules was initially assessed with the help of AutoDock Vina algorithm. Further Glide module is used to redock the previously docked complexes. The binding energies and other physiochemical properties of the designed molecules were evaluated using the Prime‐MM/GBSA and the QikProp module, respectively. The results of docking revealed the nature, site of interaction and the binding affinity between the proposed candidates and the active site of PrpR. Further the inhibitory effect of the scaffolds was predicted and evaluated employing a machine learning‐based algorithm and was used accordingly. Further, the molecular dynamics simulation studies ascertained the binding characteristics of the unique 13, when analysed across a time frame of 100 ns with GROMACS software. The results show that the proposed 1,3‐thiazetidine derivatives such as 10, 11, 13 and 14 could be potent and selective anti‐tubercular agents as compared to the standard drug Pyrazinamide. Finally, this study concludes that designed thiazetidines can be employed as anti‐tubercular agents. Undeniably, the results may guide the experimental biologists to develop safe and non‐toxic drugs against tuberculosis by demanding further in vivo and in vitro analyses.

Tuberculosis (TB) continues to be a significant global health concern with about 1.5 million deaths annually. Despite efforts to develop more efficient vaccines, reliable diagnostics, and chemotherapeutics, tuberculosis has become a concern to world health due to HIV, the rapid growth of bacteria that are resistant to treatment, and the recently introduced COVID-19 pandemic. As is well known, advances in synthetic organic chemistry have historically enabled the production of important life-saving medications that have had a tremendous impact on patients’ lives and health all over the world. Small-molecule research as a novel chemical entity for a specific disease target offers in-depth knowledge and potential therapeutic targets. In this viewpoint, we concentrated on the synthesis of a number of heterocycles reported in the previous decade and the screening of their inhibitory action against diverse strains of Mycobacterium tuberculosis. These findings offer specific details on the structure-based activity of several heterocyclic scaffolds backed by their in vitro tests as a promising class of antitubercular medicines, which will be further useful to build effective treatments to prevent this terrible illness.