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These endeavours offer the prospect of discovering new drug candidates that could outperform existing anti-infective and anticancer medications in terms of safety and efficacy. The widely held belief in the potential superiority of agents capable of modulating multiple biological targets has led to the adoption of molecular hybridization as an effective technique in the realm of drug discovery and development. While significant strides have been taken in synthesizing potential hybrid anti-HIV drugs, it is pertinent to acknowledge that no such drug has yet progressed to the development stage or preclinical trials. [Extracted from the article]

The search for new chemotherapeutics against leukemia is of great interest to researchers, owing to the limitation of the current drugs. In this research, new drug candidates against leukemia were probed through liquid chromatography-mass spectrometer (LC-MS) analysis of three traditional herbal concoctions, that provide the phytochemical profile of the samples. The identified compounds from the LC-MS were modeled for the analysis of their antileukemia activities, by using five different consensus methods, to combine the seven docking scores. The consensus methods are used to combine the docking scores to avoid losing promising drug candidates, due to a poor reproducibility of the docking scores across the different packages, due to differences in the scoring functions and training sets across the docking packages. The libraries of the potential drug candidates from the concoctions were constructed by searching the NIST database for molecules with a similar MS fragmentation. Venetoclax and gilteritinib, that target FLT3 and BCL-2 were ranked among the top hits, indicating the efficiency of this protocol without missing any potential drug. The results ranked rescinnamine and bisacodyl as new potential antileukemia agents that targets FLAT3, and BCL-2, including the mutated BCL-2 G101V receptor, that is known to be resistant to treatment with venetoclax. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a multifaceted metabolic disorder that remains a major threat to global health security. Sadly, the clinical relevance of available drugs is burdened with an upsurge in adverse effects; hence, inhibiting the carbohydrate-hydrolyzing enzymes α-glucosidase and α-amylase while preventing oxidative stress is deemed a practicable strategy for regulating postprandial glucose levels in DM patients. We report herein the α-glucosidase and α-amylase inhibition and antioxidant profile of quinoline hybrids 4a–t and 12a–t bearing 1,3,4-oxadiazole and 1,2,3-triazole cores, respectively. Overall, compound 4i with a bromopentyl sidechain exhibited the strongest α-glucosidase inhibition (IC50 = 15.85 µM) relative to reference drug acarbose (IC50 = 17.85 µM) and the best antioxidant profile in FRAP, DPPH, and NO scavenging assays. Compounds 4a and 12g also emerged as the most potent NO scavengers (IC50 = 2.67 and 3.01 µM, respectively) compared to gallic acid (IC50 = 728.68 µM), while notable α-glucosidase inhibition was observed for p-fluorobenzyl compound 4k (IC50 = 23.69 µM) and phenyl-1,2,3-triazolyl compound 12k (IC50 = 22.47 µM). Moreover, kinetic studies established the mode of α-glucosidase inhibition as non-competitive, thus classifying the quinoline hybrids as allosteric inhibitors. Molecular docking and molecular dynamics simulations then provided insights into the protein–ligand interaction profile and the stable complexation of promising hybrids at the allosteric site of α-glucosidase. These results showcase these compounds as worthy scaffolds for developing more potent α-glucosidase inhibitors with antioxidant activity for effective DM management. [ABSTRACT FROM AUTHOR]

This study reports the synthesis and characterization of novel ruthenium (II) complexes with the polydentate dipeptide, L-carnosine (2-[(3-aminopropanoyl)amino]-3- (1H-imidazol-5-yl)propanoic acid). Mixed-ligand complexes with the general composition [MLp(Cl)q(H2O)r]·xH2O (M = Ru(II); L = L-carnosine; p = 3 - q; r = 0-1; and x = 1-3) were prepared by refluxing aqueous solutions of the ligand with equimolar amounts of ruthenium chloride (black-alpha form) at 60 °C for 36 h. Physical properties of the complexes were characterized by elemental analysis, DSC/TGA, and cyclic voltammetry. The molecular structures of the complexes were elucidated using UV-Vis, ATR-IR, and heteronuclear NMR spectroscopy, then confirmed by density function theory (DFT) calculations at the B3LYP/LANL2DZ level. Two-dimensional NMR experiments (¹H COSY, 13C gHMBC, and 15N gHMBC) were also conducted for the assignment of chemical shifts and calculation of relative coordination-induced shifts (RCIS) by the complex formed. According to our results, the most probable coordination geometries of ruthenium in these compounds involve nitrogen (N1) from the imidazole ring and an oxygen atom from the carboxylic acid group of the ligand as donor atoms. Additional thermogravimetric and electrochemical data suggest that while the tetrahedral-monomer or octahedral-dimer are both possible structures of the formed complexes, the metal in either structure occurs in the (2+) oxidation state. Resulting RCIS values indicate that the amidecarbonyl, and the amino-terminus of the dipeptide are not involved in chelation and these observations correlate well with theoretical shift predictions by DFT. [ABSTRACT FROM AUTHOR]

The prognosis for patients with metastatic melanoma remains very poor. Constitutive signal transducer and activator of transcription 3 (STAT3) activation has been correlated to metastasis, poor patient survival, larger tumor size, and acquired resistance against vemurafenib (PLX-4032), suggesting its potential as a molecular target. We recently designed a series of isoseleno- and isothio-urea derivatives of several biologically active heterocyclic scaffolds. The cytotoxic effects of lead isoseleno- and isothio-urea derivatives (compounds 1 and 3) were studied in a panel of five melanoma cell lines, including B-RAFV600E-mutant and wild-type (WT) cells. Compound 1 (IC50 range 0.8–3.8 µM) showed lower IC50 values than compound 3 (IC50 range 8.1–38.7 µM) and the mutant B-RAF specific inhibitor PLX-4032 (IC50 ranging from 0.4 to >50 µM), especially at a short treatment time (24 h). These effects were long-lasting, since melanoma cells did not recover their proliferative potential after 14 days of treatment. In addition, we confirmed that compound 1 induced cell death by apoptosis using Live-and-Dead, Annexin V, and Caspase3/7 apoptosis assays. Furthermore, compound 1 reduced the protein levels of STAT3 and its phosphorylation, as well as decreased the expression of STAT3-regulated genes involved in metastasis and survival, such as survivin and c-myc. Compound 1 also upregulated the cell cycle inhibitor p21. Docking studies further revealed the favorable binding of compound 1 with the SH2 domain of STAT3, suggesting it acts through STAT3 inhibition. Taken together, our results suggest that compound 1 induces apoptosis by means of the inhibition of the STAT3 pathway, non-specifically targeting both B-RAF-mutant and WT melanoma cells, with much higher cytotoxicity than the current therapeutic drug PLX-4032. [ABSTRACT FROM AUTHOR]