Multidrug resistance (MDR) proteins related to the ATP-binding cassette family are found in a very wide range of human tumors and result in therapeutic failure. The overexpression of efflux pumps such as ABCB1 is one of the mechanisms of MDR. This paper aims to develop a reliable quantitative structure-activity relationship (QSAR) model that best describes the correlation between the activity and the molecular structures in order to predict the inhibitory biological activity towards ABCB1. In this regard, a series of quinoline derivatives of 18 compounds were analyzed using different linear and non-linear machine learning (ML) regression methods including k-nearest neighbors (KNN), decision tree (DT), back propagation neural networks (BPNN) and gradient boosting-based (GB) methods. Their aim is to explain the origin of the activity of these investigated compounds and therefore, design new quinoline derivatives with higher effect on ABCB1. A total of 16 ML predictive models were developed on different number of 2D and 3D descriptors and were evaluated using the coefficient of determination (R²) and the root mean squared error (RMSE) statistical metrics. Among all developed models, A GB-based model in particular catboost achieved the highest predictive quality, with one descriptor, expressed by R² and RMSE of 95% and 0.283 respectively. Molecular docking studies against the target crystal structure of the outward-facing p-glycoprotein (6C0V) revealed significant binding affinities via both hydrophobic and H-bond interactions with the relevant compounds. The 17 has shown the highest binding energy of -9.22 kcal/mol. Therefore, it can suggest that 17 may prove to be a valuable potential lead structure for the design and synthesis of more potent P-glycoprotein inhibitors for combination used with anti-cancer drugs for cancer multidrug resistance management.

The goal of this study was to synthesize and evaluate new antimicrobial compounds. We specifically focused on the development of 2,5-disubstituted tetrazole derivatives containing the O-methyl-2,3-O-isopropylidene-(D)-ribofuranoside groups through N-alkylation reactions. The synthesized compounds were characterized using ¹H and ¹³C nuclear magnetic resonance (NMR) spectroscopy. Their antibacterial activity was tested against Pseudomonas aeruginosa, Escherichia coli, Streptococcus fasciens, and Staphylococcus aureus. Density functional theory (DFT) was applied to examine the electronic properties, including the highest occupied molecular orbital (HOMO)-least unoccupied molecular orbital (LUMO) gap, hardness, softness, density of states (DOS), and molecular electrostatic potential. Additionally, crystal structure modeling of protein 7AZ5 was performed to study the binding affinities through hydrophobic interactions and hydrogen bonding. Molecular dynamics simulations were carried out for 100 ns and OPLS_2005 force field re performed to investigate the stability of 3c and 5c into 7AZ5 binding site. Root-mean-square deviation (RMSD), root mean square fluctuation (RMSF), and intermolecular interactions analysis showed that these two compounds may gave relative stability into the 7AZ5 binding site. Several of the N-ribofuranosyl tetrazole derivatives synthesized displayed a strong antibacterial activity. Compounds 1c and 5c were particularly effective, with a minimum inhibitory concentration (MIC) of 15.06 μM and 13.37 μM, respectively, against E. coli and S. aureus both surpassing the efficacy of chloramphenicol (19.34 μM) and ampicillin (28.62 μM). These compounds also displayed the highest binding energies in protein modeling, indicating strong interactions with the DNA polymerase sliding clamp of E. coli. Compounds 1c and 5c show promise as potent antibacterial agents with notable chemical stability and favorable binding profiles. These findings suggest that these derivatives may serve as valuable leads for the development of new antimicrobial drugs.

This study reports the synthesis of 2-thioxo-1,3-dithiol-carboxamides (TDTCAs) under mild conditions at room temperature using HBTU as a coupling agent, which significantly improved amide bond formation. The synthesized compounds were characterized using several analytical techniques, including ¹H and ¹³C NMR spectroscopy, and HRMS, confirming their intended structures and structural integrity. A DFT computational study at the B3LYP/6-31G(d,p) level was conducted on the four synthesized compounds to compare their electronic properties and molecular structures. The results showed that these compounds demonstrated antispasmodic effects on jejunum contractions. Molecular docking revealed that compounds c and d displayed the highest docking scores on potassium and voltage-gated calcium channels and adrenergic receptors. In summary, compounds c and d exhibit antispasmodic effects, potentially blocking alpha-adrenergic receptors and calcium channels, thus providing a scientific basis for their potential use in treating gastrointestinal disorders.