Compounds 4k Research Articles

Synthesis of new 3-(4-methyl-2-arylthiazol-5-yl)-5-aryl-1,2,4-oxadiazole derivatives as potential cytotoxic and antimicrobial agents

Globally cancer is the second leading cause of death; a drug that can cure cancer with the utmost negligible side effects is still a distant goal. Due to increasing antibiotic resistance, microbial infection remains a grave global health security threat. The ongoing coronavirus pandemic increased the risk of microbial and fungal infection. A new series of 3-(4-methyl-2-arylthiazol-5-yl)-5-aryl-1,2,4-oxadiazole (7a-t) have been synthesized. The structure of synthesized compounds was confirmed by the spectrometric analysis. The newly synthesized compounds were screened for cytotoxic activity against breast cell lines MCF-7 and MDA-MB-231. Against the MCF-7 ​cell line compounds 7f, 7 ​g and 7n showed excellent activity with GI50 0.6 ​μM to <100 ​nM concentration. Compound 7b showed good activity against MDA-MB-231 ​cell line with GI50 47 ​μM. The active derivatives 7b, 7e, 7f, 7 ​g and 7n were further evaluated for cytotoxicity against the epithelial cell line derived from the human embryonic kidney (HEK 293) and were found nontoxic. The thiazolyl-1,2,4-oxadiazole derivatives were also screened to evaluate theirs in vitro antimicrobial potential against Escherichia coli (NCIM 2574), Proteus mirabilis (NCIM 2388), Bacillus subtilis (NCIM 2063), Staphylococcus albus (NCIM 2178), Candida albicans (NCIM 3100) and Aspergillus niger (ATCC 504). Amongst the 7a-t derivatives, six compounds 7a, 7d, 7f, 7n, 7o, 7r showed good antifungal activity against C. albicans and eight compounds 7c, 7d, 7 ​g, 7h, 7i, 7k, 7l and 7o showed good activity against A. niger. The potential cytotoxic and antifungal activity suggested that the thiazolyl-1,2,4-oxadiazole derivatives could assist in the development of lead compounds for the treatment of cancer and microbial infections.

Synthesis, characterization, crystal structure and biological evaluation of 1,3,5-triazine-quinoline derivatives as butyrylcholinesterase inhibitors

Sixteen new 1,3,5-triazine-quinoline derivatives were designed and synthesized and evaluated as cholinesterase inhibitors. The structure of 1,3,5-triazine-quinoline derivatives were confirmed by IR, NMR, HRMS and single crystal X-ray diffraction experiments. Compound 5j had a monoclinic crystal system and P21/c space group. Compound 5k had a monoclinic crystal system and C2/c space group. The cholinesterase inhibitory activity of the synthetic compounds were measured using the colorimetric Ellman's method. Compound 5 g showed best acetylcholinesterase inhibitory activity with IC50 value of 10.82 μM and butyrylcholinesterase inhibitory activity with IC50 value of 0.046 μM. Molecular docking showed that the compound 5 g could interacted with the active site of butyrylcholinesterase.

Semisynthesis, biological activities, and mechanism studies of Mannich base analogues of magnolol/honokiol as potential α-glucosidase inhibitors

Magnolol and honokiol, derived from a Magnolia officinalis Rehd. et Wils, are a class of natural biphenolic lignans. Currently, the discovery of new α-glucosidase inhibitors from natural analogues is of interest. Here, four series of thirty new Mannich base analogues of magnolol/honokiol were prepared and evaluated for their α-glucosidase inhibitory activities. Among these Mannich base analogues of magnolol/honokiol, 3k and 3l exhibited more potent inhibitory effects on α-glucosidase than the reference drug acarbose, and their IC50 values were 14.94 ± 0.17 µM and 13.78 ± 1.42 µM, respectively. Some interesting structure–activity relationships (SARs) were also analyzed. The enzyme inhibition kinetics indicated that 3k and 3l were noncompetitive inhibitors. This result was in agreement with molecular docking studies, where the binding sites of 3k and 3l to α-glucosidase were different from that of the competitive inhibitor acarbose to α-glucosidase. Moverover, compounds 3k and 3l exhibited low toxicity to normal cells (LO2). Thus, analogues 3k and 3l could be deeply developed for the discovery of natural products based antidiabetic candidates.

Novel 1,2,4-triazole clubbed with 1,3,4-oxadiazole motifs as efficient antimicrobial agents from N-arylsydnone as synthon

1,2,4-Triazoles and 1,3,4-oxadiazoles independently are very important pharmacophores. In view of this, a new class of 1,2,4-triazole clubbed with 1,3,4-oxadiazole motifs have been prepared and characterized by IR, 1H NMR, 13C NMR and mass spectral analysis. Molecular docking of all the title compounds into S. aureus tyrosyl-tRNA synthetase (PDB: 1JIJ) and lanosterol 14α-demethylase complex with standard inhibitor Fluconazole (PDB: 3KHM) was performed which snugly fitted into the active site thus explaining their excellent inhibitory activity exhibiting their possible antibacterial and antifungal activity, respectively. Drug-likeliness, Drug score values and toxicity prediction analyses of all the title compounds have shown favourable values and these molecules belong to Class 4 and Class 5 categories which make them useful scaffolds. Interestingly, the compounds 7h, 7i, 7k, 7u and 7v have exhibited majestic antibacterial activity. Also, these compounds have shown antifungal activity against all pathogenic fungal strains with lower MIC value ranging from 0.50 - 4.00 µg/mL.

Synthesis, Characterization, and Biological Evaluation of Tetrahydropyrimidines: Dual-Activity and Mechanism of Action.

In this paper, the synthesis, characterization, and biological evaluation of the novel tetrahydropyrimidines—THPMs are described. THPMs are well-known for wide pharmacological activities such as antimicrobial, anticancer, antiviral, etc. This research includes obtained results of in vitro antimicrobial, anticancer, and α-glucosidase inhibitory activities of the eleven novel THPMs. An antibiotic assessment was done against five bacteria (two Gram-positive and three Gram-negative) and five fungi by determining the minimal inhibitory concentration (MIC), using the broth tube dilution method. The most active antibacterial compounds were 4a, 4b, and 4d, while the best antifungal activity was shown by 4e, 4f, and 4k. The lowest MIC value (0.20 mg/mL) was measured for 4e, 4f, and 4k against the Trichophyton mentagrophytes. Moreover, examining the α-glucosidase inhibitory activity revealed the compound 4g as the one with the best activity. The cytotoxic activity was performed on the tumor cell lines (HeLa, K562, and MDA-MB-231) and normal cells (MRC-5). The best antitumor activity was shown by compounds 4b and 4k against HeLa cell lines. The influence on cell cycle and mechanism of action of the most active compounds were examined too. Compound 4b had good antibacterial and anticancer activities, while 4k showed promising antifungal and anticancer activities.

Novel 18β-glycyrrhetinic acid amide derivatives show dual-acting capabilities for controlling plant bacterial diseases through ROS-mediated antibacterial efficiency and activating plant defense responses

Natural products have long been a crucial source of, or provided inspiration for new agrochemical discovery. Naturally occurring 18β-glycyrrhetinic acid shows broad-spectrum bioactivities and is a potential skeleton for novel drug discovery. To extend the utility of 18β-glycyrrhetinic acid for agricultural uses, a series of novel 18β-glycyrrhetinic acid amide derivatives were prepared and evaluated for their antibacterial potency. Notably, compound 5k showed good antibacterial activity in vitro against Xanthomonas oryzae pv. oryzae (Xoo, EC50=3.64 mg L–1), and excellent protective activity (54.68%) against Xoo in vivo. Compound 5k induced excessive production and accumulation of reactive oxygen species in the tested pathogens, resulting in damaging the bacterial cell envelope. More interestingly, compound 5k could increase the activities of plant defense enzymes including catalase, superoxide dismutase, peroxidase, and phenylalanine ammonia lyase. Taken together, these enjoyable results suggested that designed compounds derived from 18β-glycyrrhetinic acid showed potential for controlling intractable plant bacterial diseases by disturbing the balance of the phytopathogen’s redox system and activating the plant defense system.

Rational Design, Synthesis and Biological Evaluation of Novel Pyrazoline-Based Antiproliferative Agents in MCF-7 Cancer Cells.

Breast cancer is a disease in which cells in the breast divide continuously without control. There are great limitations in cancer chemotherapy. Hence, it is essential to search for new cancer therapeutics. Herein, a novel series of EGFR/HER2 dual inhibitors has been designed based on the hybridization of thiazole and pyrazoline fragments. The synthesized compounds were screened for their anti-proliferative activity against MCF-7 breast cancer cell line and MCF-10 normal breast cell line. Interestingly, synthesized compounds 6e and 6k showed very potent antiproliferative activity towards MCF-7 with IC50 values of 7.21 and 8.02 µM, respectively. Furthermore, enzymatic assay was performed against EGFR and HER2 to prove the dual inhibitory action. Compounds 6e and 6k showed potent inhibitory activity for EGFR with IC50 of 0.009 and 0.051 µM, respectively, and for HER2 with IC50 of 0.013 and 0.027 µM, respectively. Additionally, compounds 6e and 6k significantly stimulated apoptotic breast cancer cell death. Compound 6e was further explored for its anticancer activity in vivo using a Xenograft model. Moreover, computational modeling studies, ADMET studies and toxicity prediction were performed to investigate their potential drug candidates.

Design, Synthesis and In Vitro Evaluation of Spirooxindole-Based Phenylsulfonyl Moiety as a Candidate Anti-SAR-CoV-2 and MERS-CoV-2 with the Implementation of Combination Studies.

The search for an effective anti-viral to inhibit COVID-19 is a challenge for the specialized scientific research community. This work investigated the anti-coronavirus activity for spirooxindole-based phenylsulfone cycloadducts in a single and combination protocols. The newly designed anti-SARS-CoV-2 therapeutics spirooxindoles synthesized by [3 + 2] cycloaddition reactions represent an efficient approach. One-pot multicomponent reactions between phenyl vinyl sulfone, substituted isatins, and amines afforded highly stereoselective anti-SARS-CoV-2 therapeutics spirooxindoles with three stereogenic centers. Herein, the newly synthesized spirooxindoles were assessed individually against the highly pathogenic human coronaviruses and proved to be highly potent and safer. Interestingly, the synergistic effect by combining the potent, tested spirooxindoles resulted in an improved antiviral activity as well as better host-cell safety. Compounds 4i and 4d represented the most potent activity against MERS-CoV with IC50 values of 11 and 23 µM, respectively. Both compounds 4c and 4e showed equipotent activity with the best IC50 against SARS-CoV-2 with values of 17 and 18 µM, respectively, then compounds 4d and 4k with IC50 values of 24 and 27 µM, respectively. Then, our attention oriented to perform a combination protocol as anti-SARS-CoV-2 for the best compounds with a different binding mode and accompanied with different pharmacophores. Combination of compound 4k with 4c and combination of compounds 4k with 4i proved to be more active and safer. Compounds 4k with 4i displayed IC50 = 3.275 µM and half maximal cytotoxic-concentration CC50 = 11832 µM. MD simulation of the most potential compounds as well as in silico ADMET properties were investigated. This study highlights the potential drug-like properties of spirooxindoles as a cocktail anti-coronavirus protocol.

Synthesis, molecular docking, ADME study, and antimicrobial potency of piperazine based cinnamic acid bearing coumarin moieties as a DNA gyrase inhibitor.

A series of novel piperazine based cinnamic acid bearing coumarin derivatives were designed and synthesized by piperazine based cinnamic acids esterification with 4-hydroxycoumarin and characterized by various spectral techniques like infrared, 1 H nuclear magnetic resonance (NMR), 13 C NMR, and mass. The novel bioactive compounds (7a-7m) screen their potential against different bacterial and fungal strains. Compound 7g (minimum inhibitory concentration [MIC] = 12.5 µg/ml) exhibited potent antibacterial activity against Escherichia colistrain. Compounds 7d, 7f, 7g, 7k, 7l, and 7m showed potent antibacterial activity against all bacterial strains. Compounds 7a, 7g, 7h, 7k, 7l, and 7m exhibited potent antifungal activity against all fungal strains. Furthermore, a molecular docking study revealed that compounds 7d, 7f, 7g, and 7k could bind to the active site of E. coli DNA gyrase subunit B protein and form hydrogen bonding with crucial amino acid residues Arg136 in the active sites. Comprehensively, our study recommends that 7d, 7f, 7g, and 7k could be a promising lead for developing more efficient antimicrobial drug candidates and DNA gyrase inhibitors.

Synthesis and effect of N-alkylation on antibacterial activity of 2-(Benzylthio) methyl-1H-benzimidazole derivatives

In pursuit the development of novel potent and selective antibacterial agents, we synthesized twelve (12) N-alkyl 2-benzylthiomethyl-1H-benzimidazole derivatives and evaluated their antibacterial activities. Their antibacterial profile was determined with minimal inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) against a small set of two (2) strains Escherichia coli (Gram negative) and Staphylococcus aureus (Gram positive). These compounds are produced by the condensation reaction of 2-benzylthiomethyl-1H-benzimidazole (5) with benzyl chloride or bromide (6) in the presence of potassium carbonate (K2CO3). The panel of twelve synthetized compounds (7a-l) were characterized by NMR 1H, 13C spectroscopy, and high-resolution mass spectrometry (HRMS). The results showed that compounds 7a, 7b, 7c, 7d, 7e, 7f, 7h, 7k, and 7l were potent against Escherichia coli and Staphylococcus aureus, with significant MICs values from 140 to 290 µg/mL. On E. coli, five (5) compounds 7b, 7f, 7i, 7k and 7l showed bactericidal effects within common an N-alkylation by R3= phenyl, methyl, and CH2OH on the benzimidazole scaffold and the benzylthiol substituted by R2= Cl or CF3. This is evidence or a probe of these chemical groups implementing the bactericidal activity.

Discovery of 2-(1-(3-Chloro-4-cyanophenyl)-1H-pyrazol-3-yl)acetamides as Potent, Selective, and Orally Available Antagonists Targeting the Androgen Receptor.

The androgen receptor (AR) antagonists are efficient therapeutics for the treatment of prostate cancer (PCa). All the approved AR antagonists to date are targeted to the ligand-binding pocket (LBP) of AR and have suffered from various drug resistances, whereas AR antagonist targeting non-LBP site of AR is conceived as a promising strategy. Through the scaffold hopping of AR LBP antagonists, the 2-chloro-4-(1H-pyrazol-1-yl)benzonitrile was designed as a new core structure for AR antagonists. A total of 46 compounds were synthesized and biologically evaluated to disclose compounds 2f, 2k, and 4c, exhibiting potent AR antagonistic activities (IC50 up to 69 nM), force against antiandrogen resistance, and untraditional targeting site of probably AR binding function 3. Therein, 4c exhibited effective tumor growth inhibition in LNCaP xenograft study upon oral administration. This work provides a novel chemical scaffold for AR antagonists and offers new perspective for the development of PCa therapy.

Synthesis, biological evaluation and molecular modeling studies of novel carbazole-benzylpiperazine hybrids as acetylcholinesterase and butyrylcholinesterase inhibitors

A novel series of carbazole-benzylpiperazine hybrids (7a–n) were synthesized and their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities were evaluated. The biological results indicated that the nature of linker between carbazole and benzylpiperazine moieties as well as the type of substitutions on the phenyl ring of benzylpiperazine moiety greatly affected the inhibitory activity and selectivity of the synthesized compounds towards eelAChE and eqBuChE enzymes. Among all the synthesized compounds, compounds 7a (IC50 = 8.9 µM) and 7e (IC50 = 5.7 µM) with fluorine substitution at meta and para positions of the phenyl ring showed the highest inhibitory activity against eelAChE and maximum inhibitory activity against eqBuChE were generated by compounds 7h (IC50 = 5.4 µM) and 7k (IC50 = 4.5 µM) with fluorine and methyl substitutions at meta position of the phenyl ring, respectively. Furthermore, kinetic analysis and molecular modeling studies revealed that the most active compound 7e acts as a mixed-type inhibitor against AChE, which suggested this compound interacted with both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE enzyme.

Synthesis of novel thiosemicarbazone derivatives and investigation of their dual AChE and MAO-B inhibitor effects.

In this study, 15 thiosemicarbazone derivatives were synthesized. Analysis of the obtained compounds was performed by means of 1 H-NMR, 13 C-NMR and high resolution mass spectroscopy (HRMS) spectroscopic methods. The inhibition effect of the obtained compounds on cholinesterase and monoaminoxidase (MAO) enzymes were investigated with in vitro methods. None of the compounds showed significant activity on the butyrylcholinesterase enzyme. On the other hand, compounds 3b, 3c, 3e, 3k, 3l, 3m, 3n and 3o displayed significant activity on acetylcholinesterase (AChE) while compounds 3f, 3i, 3k, 3l, 3m, 3n, 3o also showed remarkable effects on monoamine oxidase-B (MAO-B) enzymes. For the selected compounds, docking studies were performed and the enzyme active site and binding modes were determined. It was revealed that the strongest interaction with AChE and MAO-B enzyme active sites was observed with the compound 3k. Another important factor in the treatment of diseases affecting the central nervous system such as Alzheimer's is the ability of the compounds to cross the blood-brain barrier (BBB). Additionally, the agents planned for the treatment of these diseases must also pass the blood-brain barrier. Therefore, in silico BBB penetration properties of active compounds were investigated.

PKM2 promotes pulmonary fibrosis by stabilizing TGF-β1 receptor I and enhancing TGF-β1 signaling.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease, and the molecular mechanisms remain poorly understood. Our findings demonstrated that pyruvate kinase M2 (PKM2) promoted fibrosis progression by directly interacting with Smad7 and reinforcing transforming growth factor–β1 (TGF-β1) signaling. Total PKM2 expression and the portion of the tetrameric form elevated in lungs and fibroblasts were derived from mice with bleomycin (BLM)–induced pulmonary fibrosis. Pkm2 deletion markedly alleviated BLM-induced fibrosis progression, myofibroblast differentiation, and TGF-β1 signaling activation. Further study showed that PKM2 tetramer enhanced TGF-β1 signaling by directly binding with Smad7 on its MH2 domain, and thus interfered with the interaction between Smad7 and TGF-β type I receptor (TβR1), decreased TβR1 ubiquitination, and stabilized TβR1. Pharmacologically enhanced PKM2 tetramer by TEPP-46 promoted BLM-induced pulmonary fibrosis, while tetramer disruption by compound 3k alleviated fibrosis progression. Our results demonstrate how PKM2 regulates TGF-β1 signaling and is a key factor in fibrosis progression.

Synthesis of Novel N-Methylmorpholine-Substituted Benzimidazolium Salts as Potential α-Glucosidase Inhibitors.

The α-glucosidase enzyme, located in the brush border of the small intestine, is responsible for overall glycemic control in the body. It hydrolyses the 1,4-linkage in the carbohydrates to form blood-absorbable monosaccharides that ultimately increase the blood glucose level. α-Glucosidase inhibitors (AGIs) can reduce hydrolytic activity and help to control type 2 diabetes. Aiming to achieve this, a novel series of 1-benzyl-3-((2-substitutedphenyl)amino)-2-oxoethyl)-2-(morpholinomethyl)-1H-benzimidazol-3-ium chloride was synthesized and screened for its α-glucosidase inhibitory potential. Compounds 5d, 5f, 5g, 5h and 5k exhibited better α-glucosidase inhibitions compared to the standard drug (acarbose IC50 = 58.8 ± 0.012 µM) with IC50 values of 15 ± 0.030, 19 ± 0.060, 25 ± 0.106, 21 ± 0.07 and 26 ± 0.035 µM, respectively. Furthermore, the molecular docking studies explored the mechanism of enzyme inhibitions by different 1,2,3-trisubstituted benzimidazolium salts via significant ligand–receptor interactions.

Design, synthesis and biological evaluation of 9-aryl-5H-pyrido[4,3-b]indole derivatives as potential tubulin polymerization inhibitors.

A series of new 9-aryl-5H-pyrido[4,3-b]indole derivatives as tubulin polymerization inhibitors were designed, synthesized, and evaluated for antitumor activity. All newly prepared compounds were tested for their anti-proliferative activity in vitro against three different cancer cells (SGC-7901, HeLa, and MCF-7). Among the designed compounds, compound 7k displayed the strongest anti-proliferative activity against HeLa cells with IC50 values of 8.7 ± 1.3 μM. In addition, 7k could inhibit the polymerization of tubulin and disrupt the microtubule network of cells. Further mechanism studies revealed that 7k arrested cell cycle at the G2/M phase and induced apoptosis in a dose-dependent manner. Molecular docking analysis confirmed that 7k may bind to colchicine binding sites on microtubules. Our study aims to provide a new strategy for the development of antitumor drugs targeting tubulin.

Bacterial FtsZ inhibition by benzo[d]imidazole-2-carboxamide derivative with anti-TB activity.

Aims: The present study aimed to assess the mode of action of previously reported anti-Mycobacterium tuberculosis benzo[d]imidazole-2-carboxamides against FtsZ along with their antibacterial potential. Materials & methods: The anti-mycobacterial action of benzo[d]imidazole-2-carboxamides against FtsZ was evaluated using inhibition of Bacillus subtilis 168, light scattering assay, circular dichroism spectroscopy, in silico molecular docking and molecular dynamics simulations. Results & conclusion: Three compounds (1k, 1o and 1e) were active against isoniazid-resistant strains. Four compounds (1h, 1i, 1o and 4h) showed >70% inhibition against B. subtilis 168. Compound 1o was the most potent inhibitor (91±5% inhibition) ofB. subtilis 168 FtsZ and perturbed its secondary structure. Molecular docking and molecular dynamics simulation of complexed 1o suggested M. tuberculosis FtsZ as a possible target for antitubercular activity.

Novel 5,6-diphenyl-1,2,4-triazine-3-thiol derivatives as dual COX-2/5-LOX inhibitors devoid of cardiotoxicity

A novel series of 5,6-diphenyl-1,2,4-triazine-3-thiol derivatives were designed, synthesized, and screened for their inhibitory potential against COX-2 and 5-LOX enzymes. The compounds from the series have shown moderate to excellent inhibitory potential against both targets. Compound 6k showed the inhibitions against COX-2 (IC50 = 0.33 ± 0.02 μM) and 5-LOX inhibition (IC50 = 4.90 ± 0.22 μM) which was better than the standard celecoxib (IC50 = 1.81 ± 0.13 μM) for COX-2 and zileuton (IC50 = 15.04 ± 0.18 μM) for 5-LOX respectively. Further investigation on the selected derivative 6k in rat paw edema models revealed significant anti-inflammatory efficacy. Compound 6k has also shown negligible ulcerogenic liability as compared to indomethacin. Moreover, in vivo biochemical analysis also established the compound’s antioxidant properties. Compounds 6c and 6k were also observed to be devoid of cardiotoxicity post-myocardial infarction in rats. The molecular docking and dynamics simulation studies of the most active derivative 6k affirmed their consentient binding interactions with COX-2 specific ravine and cleft of 5-LOX.

Development of novel 9-O-substituted-13-octylberberine derivatives as potential anti-hepatocellular carcinoma agents

A series of novel 9-O-substituted-13-octylberberine derivatives were designed, synthesised and evaluated for their anti-hepatocellular carcinoma (HCC) activities. Compound 6k showed the strongest activity against three human hepatoma cells including HepG2, Sk-Hep-1 and Huh-7 cells with IC50 values from 0.62 to 1.69 μM, which were much superior to berberine (IC50 >50 μM). More importantly, 6k exhibited lower cytotoxicity against normal hepatocytes L-02 with good lipid-water partition properties. The mechanism studies revealed that 6k caused G2/M phase arrest of the cell cycle, stabilised G-quadruplex DNA, and induced apoptosis via a mitochondrial apoptotic pathway. Finally, the in vivo anti-HCC activity of 6k was validated in the H22 liver cancer xenograft mouse model. Collectively, the current study would provide a new insight into the discovery of novel, safe and effective anti-HCC agents.

α-Glucosidase and α-Amylase Inhibitory Potentials of Quinoline-1,3,4-oxadiazole Conjugates Bearing 1,2,3-Triazole with Antioxidant Activity, Kinetic Studies, and Computational Validation.

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.