The development of multifunctional small molecules with combined anti-inflammatory, antioxidant, and antitubercular potential remains an important strategy in medicinal chemistry. Acridone and 1,2,3-triazole scaffolds are well recognized for their diverse biological activities; however, amide-functionalized 1,2,3-triazole-acridone conjugates have been insufficiently explored for their therapeutic potential. In this study, a focused library of amide-functionalized 1,2,3-triazole-acridone conjugates 8a-n was designed and synthesized via a click chemistry approach to investigate their biological activities and structure-activity relationships. Evaluation revealed that conjugates 8a, 8b, 8f, 8i, and 8k exhibited significant in vitro anti-inflammatory activity, while 8a and 8k demonstrated the strongest antioxidant activity among the synthesized derivatives. None of the synthesized compounds showed appreciable antitubercular activity. Molecular docking studies supported the observed biological activities by revealing favorable interactions of the active conjugates with the target protein. Density functional theory (DFT) calculations provided insight into the electronic properties, molecular electrostatic potential, and frontier molecular orbitals, while molecular dynamics simulations confirmed the stable binding of the most active conjugate, 8k, within the target binding site. This study introduces a new class of amide-functionalized 1,2,3-triazole-acridone conjugates and demonstrates the synergistic integration of biological evaluation with computational investigations to establish the structure-activity relationships. The findings identify conjugate 8k as a promising lead for the development of novel anti-inflammatory and antioxidant agents and provide a rational framework for the future optimization of this molecular scaffold.
Target-directed disruption of the VEGFR2 kinase cascade remains a cornerstone strategy in anti-angiogenic oncology therapeutics; however, severe systemic toxicities, acquired resistance profiles of current drugs, and tedious multi-step chromatographic isolation bottlenecks in hybrid molecule synthesis present major ongoing challenges. To address these limitations, this study presents the rational design and efficient fabrication of a novel series of heterocyclic azo-imine hybrids (3a-j) through a high-yield (92-78%), chromatography-free one-pot acid-catalyzed condensation protocol. These scaffolds strategically integrate an Imatinib-inspired aniline core to evaluate their multi-kinase inhibitory potential against the VEGFR2 cascade. Quantum chemical simulations, executed within the DFT framework at the B3LYP/6-311++G(d,p) level of theory in DMSO continuum, mapped the fundamental electronic topology, global reactivity profiles, and intramolecular charge transfer (ICT) gradients of the library. Molecular docking simulations against the inactive 'DFG-out' state of VEGFR2 (PDB ID: 4ASD) demonstrated exceptional geometric complementarity, outperforming the reference drug Sorafenib in binding affinity (up to -13.1 kcal/mol). Thermodynamic binding free energy calculations identified ligand 3h as the most exergonic binder (Delta Gbind = -98.662 kJ/mol vs. Sorafenib: -54.029 kJ/mol), while an explicit 250-ns molecular dynamics simulation trajectory confirmed high structural resilience and steady induced-fit adaptations under dynamic biological conditions. Collectively, these findings support the potential of these novel scaffolds as VEGFR2-targeting compounds and warrant further experimental investigation to establish their biological activity.
A novel series of 1,2,3-triazole-pyrazolo[1,5-a]pyridine based on targeting antibacterial and antifungal activity was rationally designed by integrating key pharmacophores into a single molecule. The target compounds (5a-5k) were efficiently prepared via a multistep synthetic route involving the condensation of pyrazolo[1,5-a]pyridine-acetyl chloride intermediate with corresponding amines, and their structures were confirmed through 1H-NMR,13C-NMR, and HRMS spectrometry. In vitro antimicrobial assessment against Klebsiella pneumoniae and Micrococcus luteus revealed that compounds 5d, 5 g, and 5k exhibited significant antibacterial activity at low minimum inhibitory concentrations (MIC, 3.85 +/- 1.67 to 6.25 +/- 1.33 & micro;M), with favorable selectivity indices highlighting preferential toward microorganisms. Compounds 5f, 5 g, and 5k exhibited most promising antifungal activity, with MIC values ranging from 4.68 +/- 1.03 to 5.2 +/- 0.77 & micro;M against Candida glabrata when compared with ketoconazole (KTZ) (MIC = 6.24 +/- 0.56 & micro;M). Molecular docking studies demonstrated good binding interactions between the synthesized compounds and the target proteins-dehydrogenase of Micrococcus luteus (PDB 6KQ9), and sterol 14 alpha-demethylase (CYP51) from Candida albicans (PDB 5FSA) offering valuable insights into their binding mechanisms. Further, to confirm the formation of a novel linkage, the electronic and structural properties of the lead-most-active compound 5a and 5k were studied by DFT calculations on the Gaussian 09 software package. Moreover, drug-likeness and potential bioavailability were assessed by using in silico ADME-toxicity analysis to evaluate the pharmacokinetic features. The key findings of the in vitro antimicrobial and molecular docking results, as well as the analysis, demonstrated that the synthesized compounds have potential antimicrobial potency and can be further optimized to serve as lead compounds.
