Computational investigation of amide derivative as potential anti-carbapenem-resistant Pseudomonas aeruginosa

Abstract

Recent findings indicate a surge in morbidity and mortality probabilities associated with infections caused by carbapenem-resistant strains, underscoring an urgent need for the development of effective drugs against these strains. This study employs Density Functional Theory (DFT) with the ωB97XD/6–311++G (2d, 2p) model to investigate the electronic, structural, and the biological potential of N 1, N10 -Bis (1,3,4-thiadiazolo (3,2-a)pyridine-2-yl)-decanediamide (TDZ). Fourier Transform Infrared Spectroscopy highlights significant assignments related to C-H, C=C, and N=H functionalities, aligning well with experimental results. Chemical reactivity analysis orders the energy gap as TDZ_Acetone > TDZ_Gas > TDZ_DMSO > TDZ_Water. The visualization of weak interaction in wider regions of steric repulsions are seen for TDZ in solvents DMSO , acetone and water as well as transformation of strong halogen bonds to van der Waals interaction . Visual findings reveal the propensity of the compound to form hydrogen bonds with protein targets due to high electron localization around hydrogen atoms . Pharmacokinetics studies indicate TDZ's favorable intestinal absorption at 50.525 %. Moreover, TDZ does not inhibit hERG 1, eliminating the risk of potassium channel blocking-induced cardiac arrhythmia . Molecular docking analysis shows TDZ's enhanced biological activity and stronger binding affinity with 5XNW, with a binding affinity of −4.5 kcal/mol and the formation of five conventional hydrogen bonds . Comparatively, for 4AKX, the standard drug Dori records eight hydrogen bond interactions at −6.8 kcal/mol, while TDZ records nine interactions at −8.6 kcal/mol. This suggests that, despite Dori's favorable interactions and good biological activity, TDZ exhibits superior binding affinity and heightened biological activity potential, positioning it as a promising drug candidate against carbapenem-resistant Pseudomonas aeruginosa infections. • Experimental and theoretical frequencies align in magnitude verifying the validity of the DFT method ωB97XD/6–311++G (2d, 2p) utilized for optimization. • Weak interactions are present for TDZ in acetone, gas, DMSO and water. • There is propensity of formation of hydrogen bonds with the compound as electron localization is high within the around hydrogen atoms. • TDZ records higher binding affinity (−8.6 kcal/mol) than Doripenem (−6.8 kcal/mol). • TDZ expressed favorable gastrointestinal absorption rates and inactive hepatotoxicity, carcinogenicity, immunogenicity, mutagenicity and cytotoxicity.