Compounds 4d Research Articles

Synthesis, physicochemical characterization, and investigation of anti-inflammatory activity of water-soluble PEGylated 1,2,4-Triazoles

A series of water-soluble PEGylated 1,2,4-triazoles 5–8 were successfully synthesized from methyl 5-(chloromethyl)-1-aryl-1H-1,2,4-triazole-3-carboxylates 1. All of the water-soluble PEGylated 1,2,4-triazoles were characterized by FT-IR and 1H NMR spectroscopy. The solubility, in vitro plasma stability, and anti-inflammatory activity were also determined and compared to original methyl 5-(halomethyl)-1-aryl-1H-1,2,4-triazole-3-carboxylates. For SAR study, all PEGylated 1,2,4-triazoles 5–8 performed potential anti-inflammatory activity on LPS-induced RAW 264.7 cells (IC50 = 3.42–7.81 μM). Moreover, the western blot result showed PEGylated 1,2,4-triazole 7d performed 5.43 and 2.37 folds inhibitory activity over iNOS and COX-2 expressions. On the other hand, the cell viability study revealed PEGylated 1,2,4-triazoles 7 and 8 with PEG molecular weight more than 600 presented better cell safety (cell viability > 95 %). Through the solubility and in vitro plasma stability studies, PEGylated 1,2,4-triazoles 7a–d exhibited higher hydrophilicity and prolonged 2.01 folds of half-life in compound 7d. Furthermore, the in vivo anti-inflammatory and gastric safety results indicated PEGylated 1,2,4-triazole 7d more effectively decreased the inflammatory response in edema and COX-2 expression and exhibited higher gastric safety than Indomethacin. Following the in vitro and in vivo study results, PEGylated 1,2,4-triazole 7d possessed favorable solubility, plasma stability features, safety, and significant anti-inflammatory activity to become the potential water-soluble anti-inflammatory candidate.

Eco-friendly green synthesis of N‑pyrazole amino chitosan using PEG-400 as an anticancer agent against gastric cancer cells via inhibiting EGFR.

The present study was conducted to develop a green process that provides access to the development of Schiff base derivatives of chitosan with the heterocyclic moiety as a novel class of anti-gastric cancer agent. In the present study, we have synthesized these derivatives by reacting various pyrazoles with chitosan using CAN in PEG400. The compounds were synthesized in 20min in excellent yield by using CAN at 5% in PEG400 at 80°C in the shortest reaction time of 20min. The PEG400 could be efficiently recycled for the three consecutive runs. The developed compounds were tested for EGFR-TK inhibition using a Kinase-Glo Plus luminescence kinase assay kit where they exhibited significant activity revealing compound 2d as the most potent analog, while other compounds showed mild to moderate inhibitory activity. MTT assay was conducted to determine the effect of the three most potent EGFR inhibitors (2b, 2c, and 2d) on the proliferation of gastric cancer cells (SGC-7901). The results showed compound 2d as the most potent anticancer agent against SGC7901 cells. The effect of compound 2d was also quantified on the apoptosis and cell phase of SGC7901 cells using flow cytometry assay at various concentrations ranging from 0, 10, 20, and 30µM. Results suggest that compound 2d showed significant inhibition of SGC-7901 by inducing apoptosis and arresting G0/G1 cell phase. The western blot analysis also revealed that compound 2d significantly inhibited the overexpression of EGFR in SGC-7901 cells. The study successfully demonstrated the development of N‑pyrazole amino chitosan as a novel class of agent against gastric cancer via inhibition of EGFR.

Design, Synthesis and In vitro Antitubercular Effect of New Chalcone Derivatives Coupled with 1,2,3-Triazoles: A Computational Docking Techniques.

A very interesting foundation for this study is the creation of new methods for modifying compounds with a 1,2,3-triazole and chalcone scaffolds, as these compounds are significant in organic synthesis, particularly in the synthesis of bioactive organic compounds. To contribute to the development of an efficient method for the conversion of antimicrobial and antituberculosis heterocyclics, a novel series of cyclohepta pyridinone fused 1,2,3-triazolyl chalcones were designed and synthesized. All the newly prepared scaffolds were characterized by FT-IR, NMR (1H & 13C) and mass spectrometry. Among the tested compounds, hybrids 8b, 8d, and 8f exhibited exceptional antibacterial susceptibilities with zone of inhibition 27.84±0.04, 32.27±0.02, and 38.26±0.01 mm against the tested E. faecalis bacteria, whereas 8d had better antitubercular potency against M. tuberculosis H37Rv strain with MIC value 5.25 μg/mL, compared to Streptomycin [MIC=5.01 μg/mL]. All the synthesized compounds were initially assessed in silico against the targeted protein i. e., DprE1 that indicated compound 8d, 8f and 8h along with several other 1,2,3-triazole compounds as possible inhibitors. Based on docking results, 8d showed that the amino acids His74(A), Lys76(A), Cys332(A), Asp331(A), Val307(A), Tyr357(A), Met226(A), Gln276(A), Gly75(A), Peo58(A), Leu259(A), and Lys309(A) exhibited highly stable binding to DprE1 receptor of Mycobacterium tuberculosis (PDB: 4G3 U). Moreover, these scaffolds physicochemical characteristics, filtration molecular properties, assessment of toxicity, and bioactivity scores were assessed in relation to ADME (absorption, distribution, metabolism, and excretion).

Design and Synthesis of Aspirin-chalcone Mimic Conjugates as Potential Anticancer Agents.

Extensive research has been conducted on aspirin, a widely recognized NSAID medication, regarding its potential as an anticancer agent. Studies have revealed its ability to trigger cell death in different types of cancer cells. A set of aspirin-chalcone mimic conjugates 5a-k and 6a-d utilizing the freshly prepared acid chloride of aspirin moiety has been designed and synthesized. To evaluate the newly developed compounds, the NCI 60- cell line panel was employed to assess their anti-proliferative properties. Subsequently, cell cycle analysis was conducted along with an examination of the compounds' impact on the levels of p53, Bax, Bcl-2, active caspase- 3, and their inhibition mechanism of tubulin polymerization. Derivative 6c displayed the best anticancer activity among the tested series while 6d was the best against breast cancer MDA-MB-468, therefore both of them were selected for the 5-dose stage, however, targeting MDA-MB-468, PI-flow cytometry of compound 6d proved the triggered cell growth arrest at the G1/S phase avoiding the mitotic cycle in MDA-MB-468 cells. Similarly, the upregulation of oncogenic parameters such as caspase-3, p53, and Bax/Bcl-2, along with the inhibition of PARP-1 enzyme level, was observed with compound 6d. This compound also exhibited a significant ability to induce apoptosis and disrupt the intracellular microtubule network through a promising activity as a tubulin polymerization inhibitor with IC50 = 1.065 ± 0.024 ng/ml. Furthermore, to examine the manner in which compound 6d binds to the active pocket of the tubulin polymerization enzyme, a molecular docking study was conducted. The study indicated that compound 6d could be a powerful microtubule-destabilizing agent. Therefore, further research on 6d could be worthwhile.

Design, synthesis and characterization of ethyl 3-benzoyl-7-morpholinoindolizine-1-carboxylate as anti-tubercular agents: In silico screening for possible target identification.

A thorough search for the development of innovative drugs to treat tuberculosis, especially considering the urgent need to address developing drug resistance, we report here a synthetic series of ethyl 3-benzoyl-7-morpholinoindolizine-1-carboxylate analogues (5a-o) as potent anti-tubercular agents. These morpholino-indolizines were synthesized by reacting 4-morpholino pyridinium salts, with various electron-deficient acetylenes to afford the ethyl 3-benzoyl-7-morpholinoindolizine-1-carboxylate analogues (5a-o). All synthesized intermediate and final compounds are characterized by spectroscopic methods such as 1H NMR, 13C NMR and HRMS and further examined for their anti-tubercular activity against the M. tuberculosis H37Rv strain (ATCC 27294-American type cell culture). All the compounds screened for anti-tubercular activity in the range of 6.25-50 μM against the H37Rv strain of Mycobacterium tuberculosis. Compound 5g showed prominent activity with MIC99 2.55 μg/mL whereas compounds 5d and 5j showed activity with MIC99 18.91 μg/mL and 25.07 μg/mL, respectively. In silico analysis of these compounds revealed drug-likeness. Additionally, the molecular target identification for Malate synthase (PDB 5CBB) is attained by computational approach. The compound 5g with a MIC99 value of 2.55 μg/mL against M. tuberculosis H37Rv emerged as the most promising anti-TB drug and in silico investigations suggest Malate synthase (5CBB) might be the compound's possible target.

Proposal, Synthesis and Antimicrobial activity of 1-((1-phenyl-1H-1,2,3-triazol-5-yl)methyl)-2-(4-phenyl-2H-chromen-3-yl)-1H-benzo[d]imidazole

A new series of 1-((1-phenyl-1H-1,2,3-triazol-5-yl) methyl)-2-(4-phenyl-2H-chromen-3-yl)-1H-benzo [d] imidazole (12a-n) and a library of novel imidazole-1,2,3-triazole hybrids were designed and synthesized based on the fusion pharmacophore approach. Therefore, copper (I) catalyzed click reaction of propargylated imidazole with numerous organo arylazides yielded imidazole-1,2,3-triazole hybrids 12a–n. The products were purified over column chromatography and structures of these compounds are recognized by IR, 1H-NMR, 13C-NMR and mass spectral data. All the final compounds were screened for their anti-microbial activity and the effects were matched with ciprofloxacin. Compound (12d, l, i) was the most effective compound of this series and with activities improved than ciprofloxacin under the experienced situations. Chroman-4-one scaffold is a stable structure in heterocyclic chemistry and drug conclusion.

Benzohydrazide as a good precursor for the synthesis of novel bioactive and anti-oxidant 2-phenyl-1,3,4-oxadiazol-aminoacid derivatives: Structural determination, biological and anti-oxidant activity

The synthesis and biological assessment of 2,5-disubstituted-1,3,4-oxadiazole derivatives from benzo hydrazide and amino acids as novel potential antioxidant and antibacterial agents have been reported. The structures of the new compounds were characterized by physicochemical properties and spectral methods. The synthesized compounds were screened for their in vitro antibacterial activity against three Gram-positive bacterial strains, namely Staphylococcus aureus ATCC 25923, Bacillus cereus ATCC 14579, Listeria innocua ATCC 33090, and two Gram-negative bacterial strains, namely Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, and antifungal activity against Candida albicans ATCC 10231 in comparison with Amoxicillin, Tetracycline, Gentamicin and Oxacillin as standards. Most of the compounds have excellent efficacy, and some of them, such as 5i, 5g, 5d, 5c, and 5j can inhibit their activity better or very close to that of Amoxicillin, Tetracycline, Gentamicin, Oxacillin used as standards. Compounds 5b and 5i provided good results against L. innocua with inhibition values of IZ = 14 mm and IZ = 22 mm, respectively, while the rest of the compounds and antibiotics were unable to inhibit it. Compounds 5c, 5d, 5g and 5j showed excellent activity against C. albicans with values between 31 mm and 34 mm. These results were better than all the standards used. The MIC value (25 µg/ml) for derivatives 5(c-e), 5g and 5(i-j) against B. cereus represent the best activity of the tested compounds. All the target compounds were also screened for radical scavenging antioxidant activities by DPPH, FRAP, and TAC assays and found to be excellent antioxidant agents. According to the results, it was observed that most derivatives synthesized showed excellent activity with a concentration of 250 µg/ml as an antioxidant agent (76 % < RSA < 95.5 %) which gave an inhibition percentage that was better or very close to that of ascorbic acid and better than BHT.

Synthesis, Cytotoxic Activity Evaluation and Molecular Docking Studies of Some Benzimidazole Derivatives

In this study, the synthesis of 2-(2-acetyl-1H-benzimidazol-1-yl)-1-arylethanone (3a-3d) and 1-methyl-3-phenyl-benzo[4,5]imidazo[1,2-a]pyrazine derivatives (4a-4d) and to investigate their cytotoxic activity were aimed. APCI, IR, 1HNMR, and 13CNMR spectra were utilized to determine the structure of the synthesized compounds. The cytotoxic activity of selected compounds were detected in A549 (human lung carcinoma) and NIH3T3 (mouse embryonic fibroblasts) cell lines. Compounds 4c and 4d were found to be selectively cytotoxic against A549 and NIH3T3 cell lines. Molecular docking studies were performed using the data retrieved from the Protein Data Bank server (PDBID: 4QTX).

Design, synthesis, and activity evaluation of 2-iminobenzimidazoles as c-Myc inhibitors for treating multiple myeloma

Multiple myeloma (MM) is a plasma cell malignancy that remains incurable and poses a significant threat to global public health. The multifunctional transcription factor c-Myc plays a crucial role in various cellular processes and is closely associated with MM progression. As part of the basic-helix-loop-helix-leucine zipper (bHLHZip) family, c-Myc forms heterodimers with its obligate partner Max, binds to the Enhancer-box (E-box) of DNA, and ultimately co-regulates gene expression. Therefore, impeding the capacity for heterodimerization to bind to DNA represents a favored strategy in thwarting c-Myc transcription. In this study, we first synthesized a series of novel 2-iminobenzimidazole derivatives and further estimated their potential anti-MM activity. Notably, among all the derivatives, 5b and 5d demonstrated remarkable inhibitory activity against RPMI-8226 and U266 cells, with IC50 values of 0.85 μM and 0.97 μM for compound 5b, and 0.96 μM and 0.89 μM for compound 5d. Western blot and dual-luciferase reporter assays demonstrated that compounds 5b and 5d effectively suppressed both c-Myc protein expression and transcriptional activity of the c-Myc promoter in RPMI-8226 and U266 cells. Furthermore, these compounds induced apoptosis and G1 cell cycle arrest in the aforementioned MM cells. Molecular docking studies revealed that 5b and 5d exhibited strong binding affinity to the interface between c-Myc/Max and E-box of DNA. Taken together, our findings suggest that further investigations are warranted for potential therapeutic applications of 5b and 5d for c-Myc-related diseases.

Identification of Novel Bisamide-Decorated Benzotriazole Derivatives as Anti-Phytopathogenic Virus Agents: Bioactivity Evaluation and Computational Simulation.

As a notorious phytopathogenic virus, the tobacco mosaic virus (TMV) severely reduced the quality of crops worldwide and caused critical constraints on agricultural production. The development of novel virucides is a persuasive strategy to address this predicament. Herein, a series of novel bisamide-decorated benzotriazole derivatives were elaborately prepared and screened. Biological tests implied that the optimized compound 7d possessed the most brilliant antiviral inactive profile (EC50 = 157.6 μg/mL) and apparently surpassed that of commercial ribavirin (EC50 = 442.1 μg/mL) 2.8-fold. The preliminary antiviral mechanism was elaborately investigated via transmission electron microscopy, microscale thermophoresis (MST) determination, RT-qPCR, and Western blot analysis. The results showed that compound 7d blocked the assembly of TMV by binding with coat protein (Kd = 0.7 μM) and suppressed TMV coat protein gene expression and biosynthesis process. Computational simulations indicated that 7d displayed strong H-bonds and pi interactions with TMV coat protein, affording a lower binding energy (ΔGbind = -17.8 kcal/mol) compared with Ribavirin (ΔGbind = -10.7 kcal/mol). Overall, current results present a valuable perception of bisamide decorated benzotriazole derivatives with appreciably virustatic competence and should be profoundly developed as virucidal candidates in agrochemical.

Pyridazine and pyridazinone derivatives: Synthesis and in vitro investigation of their anti-inflammatory potential in LPS-induced RAW264.7 macrophages.

New pyridazine and pyridazinone derivatives 3a-g, 4a-f, 6a, and 6b were designed and synthesized. Cell viability of all compounds was established based on the viability of lipopolysaccharide-induced RAW264.7 macrophage cells determined via the MTT assay. In vitro inhibition assays on human COX-1 and COX-2 enzymes were conducted to probe the newly synthesized compounds' anti-inflammatory activity. The half maximal inhibitory concentration values for the most active compounds, 3d, 3e, and 4e towards COX-2 were 0.425, 0.519, and 0.356 µM, respectively, in comparison with celecoxib. The newly synthesized compounds' ability to inhibit the production of certain proinflammatory cytokines, such as inducible nitric oxide synthase, tumor necrosis factor-α, interleukin-6, and prostaglandin-E2, was also estimated in lipopolysaccharide-induced macrophages (RAW264.7 cells). Compounds 3d and 3e were identified as the most potent cytokine production inhibitors. The results of molecular modeling studies suggested that these compounds were characterized by a reasonable binding affinity toward the active site of COX-2, when compared to a reference ligand. These results might be taken into consideration in further investigations into new anti-inflammatory agents.

Antioxidant and antibacterial activities of 5-mercapto(substitutedthio)-4-substituted-1,2,4-triazol based on nalidixic acid: A comprehensive study on its synthesis, characterization, and In silico evaluation

This study introduces a series of novel Alkyl thio-1,2,4-triazole (4a-p) and mercapto-1,2,4-triazole (3a-d) compounds derived from nalidixic acid. The synthesis was streamlined, involving interactions between nalidixic acid hydrazide and various isothiocyanates to yield cyclic and alkyl(aryl) sulfide compounds, characterized using 1H NMR, 13C NMR, IR, and elemental analysis. Antioxidant capabilities were quantified through DPPH and ABTS assays, highlighting significant potential, especially for compound 3d, which demonstrated an ABTS IC50 value of 0.397 μM, on par with ascorbic acid (IC50 = 0.87 μM). Antibacterial efficacy was established through MIC assessments against a broad spectrum of Gram-positive and Gram-negative bacteria, including Candida albicans. Compounds 3b, 4e, 4h, 4j, 4i, 4m, and 4o showed broad-spectrum activity, with 4k and 4m exhibiting pronounced potency against E. coli. Molecular docking studies validated the antibacterial potential, with compounds 4f and 4h showing high binding affinities (docking scores of −9.8 and −9.6 kcal/mol, respectively), indicating robust interactions with the bacterial enzyme targets. These scores underscore the compounds' mechanistic basis for their antibacterial action and support their therapeutic promise. Furthermore, compounds 3b, 4i, and 4m, identified through drug-likeness and toxicity predictions, were highlighted for their favorable profiles, suggesting their suitability for oral antibiotic therapies. This comprehensive study, blending synthetic, in vitro, and in silico approaches, emphasizes the triazole derivatives' potential as future candidates for antibiotic and antioxidant applications, particularly spotlighting compounds 3b, 4i, and 4m due to their promising efficacy and safety profiles.

Synthesis, Glucosidase Inhibition, and In Silico Modeling Analysis of Highly Fluorinated 2-Imino-1,3-thiazolines in Search of Potent Antidiabetic Agents.

In the present work, 2-imino-1,3-thiazolines featuring highly fluorinated fragments were synthesized through a straightforward cyclization of diversely substituted thioureas with 2-bromo-1-(4-fluorophenyl)ethan-1-one. The target compounds were obtained in good yields, and structures were established by FTIR and 1H- and 13C NMR spectroscopic methods. The in vitro biological assay revealed that all the compounds significantly obstruct the α-glucosidase. Compound 6d (3-fluoro-N-(3-(2-fluorophenyl)-4-(4-fluorophenyl)thiazol-2(3H)-ylidene)benzamide) showed the highest antidiabetic potential with an IC50 value of 1.47 ± 0.05 μM. In addition, computational analysis revealed the binding energy of -11.1 kcal/mol for 6d which was lower than the positive standard, acarbose (-7.9 kcal/mol). Several intermolecular interactions between the active site residues and 6d highlight the significance of 2-imino-1,3-thiazoline core in attaining the potent efficacy and making these compounds a valuable pharmacophore in drug discovery.

Novel 6-alkyl-bridged 4-arylalkylpiperazin-1-yl derivatives of azepino[4,3-b]indol-1(2H)-one as potent BChE-selective inhibitors showing protective effects against neurodegenerative insults

Due to the putative role of butyrylcholinesterase (BChE) in regulation of acetylcholine levels and functions in the late stages of the Alzheimer's disease (AD), the potential of selective inhibitors (BChEIs) has been envisaged as an alternative to administration of acetylcholinesterase inhibitors (AChEIs). Starting from our recent findings, herein the synthesis and in vitro evaluation of cholinesterase (ChE) inhibition of a novel series of some twenty 3,4,5,6-tetrahydroazepino[4,3-b]indol-1(2H)-one derivatives, bearing at the indole nitrogen diverse alkyl-bridged 4-arylalkylpiperazin-1-yl chains, are reported. The length of the spacers, as well as the type of arylalkyl group affected the enzyme inhibition potency and BChE/AChE selectivity. Two compounds, namely 14c (IC50 = 163 nM) and 14d (IC50 = 65 nM), bearing at the nitrogen atom in position 6 a n-pentyl- or n-heptyl-bridged 4-phenethylpiperazin-1-yl chains, respectively, proved to be highly potent mixed-type inhibitors of both equine and human BChE isoforms, showing more than two order magnitude of selectivity over AChE. The study of binding kinetics through surface plasmon resonance (SPR) highlighted differences in their BChE residence times (8 and 47 s for 14c and 14d, respectively). Moreover, 14c and 14d proved to hit other mechanisms known to trigger neurodegeneration underlying AD and other CNS disorders. Unlike 14c, compound 14d proved also capable of inhibiting by more than 60% the in vitro self-induced aggregation of neurotoxic amyloid-β (Aβ) peptide at 100 μM concentration. On the other hand, 14c was slightly better than 14d in counteracting, at 1 and 10 μM concentration, glutamate excitotoxicity, due to over-excitation of NMDA receptors, and hydrogen peroxide-induced oxidative stress assessed in neuroblastoma cell line SH-SY5Y. This paper is dedicated to Prof. Marcello Ferappi, former dean of the Faculty of Pharmacy of the University of Bari, in the occasion of his 90th birthday.

Exploring rhodanine linked enamine-carbohydrazide derivatives as mycobacterial carbonic anhydrase inhibitors: Design, synthesis, biological evaluation, and molecular docking studies.

With the rise of multidrug-resistant tuberculosis, the imperative for an alternative and superior treatment regimen, incorporating novel mechanisms of action, has become crucial. In pursuit of this goal, we have developed and synthesized a new series of rhodanine-linked enamine-carbohydrazide derivatives, exploring their potential as inhibitors of mycobacterial carbonic anhydrase. The findings reveal their efficacy, displaying notable selectivity toward the mycobacterial carbonic anhydrase 2 (mtCA 2) enzyme. While exhibiting moderate activity against human carbonic anhydrase isoforms, this series demonstrates promising selectivity, positioning these compounds as potential antitubercular agents. Compound 6d was the best one from the series with a Ki value of 9.5 µM toward mtCA 2. Most of the compounds displayed moderate to good inhibition against the Mtb H37Rv strain; compound 11k showed a minimum inhibitory concentration of 1 µg/mL. Molecular docking studies revealed that compounds 6d and 11k show metal coordination with the zinc ion, like classical CA inhibitors.

Design, synthesis and anti-oomycete activity of 2-acyloxyhinokitiol derivatives

In order to explore novel natural product-based anti-oomycete agent, ten 2-acyloxyhinokitiol derivatives (5a–j) were designed and synthesised, and structurally confirmed by 1H NMR,13C NMR, HRMS, and melting point. The stereochemical configuration of compound 5f was unambiguously confirmed by single-crystal X-ray diffraction. Furthermore, we evaluated the target compounds 5a–j as anti-oomycete activity against a serious agricultural disease of Phytophthora capsici. Among the ten hinokitiol ester derivatives tested, four compounds 5d, 5g, 5h and 5j had anti-oomycete activity higher than the positive control zoxamide (EC50 = 23.59 mg/L), and the EC50 values of 18.90, 20.62, 13.61 and 21.29 mg/L, respectively. Especially compound 5h exhibited the best anti-oomycete activity against P. capsici with EC50 value of 13.61 mg/L. Overall, the anti-oomycete activities of 2-acyloxyhinokitiol derivatives is higher than that of 2-sulfonyloxyhinokitiol derivatives. The results laid a good foundation for the subsequent synthesis of hinokitiol ester derivatives with significant anti-oomycete activity.

Synthesis and antibacterial evaluation of new naphthalimide-coumarin hybrids against multidrug-resistant S. aureus and M. tuberculosis

The rapid rise in antimicrobial resistance (AMR) has become a major threat to human health. Consequently, the constant search for new antibacterial agents that work against resistant organisms has become a global initiative. To discover new antibacterial agents with improved efficacy and activity against drug-resistant organisms, we designed and synthesized a series of new naphthalimide-coumarin hybrids and evaluated them for their antimicrobial activity against a panel of bacterial and mycobacterial strains. In the preliminary evaluation, compounds 7a, 7c, 7d, 7e, 7f, 7h, 7i, 7o, 7q, 20a and 20b exhibited potent inhibitory activity against S. aureus ATCC 29213 with MICs in the range of 0.5–32 µg/mL. Compounds 7c, 7d, 7f, 7h, 7i, 7o, 20a, and 20b also exhibited good inhibitory activity against S. epidermidis with MIC 1–16 µg/mL. All these compounds were found to be non-toxic to Vero cells (CC50 = >50) and exhibited a favorable selectivity index (SI = >12.5). Additionally, these compounds 7c, 7d, 7e, 7f, 7h, 7i, 7o, 20a and 20b have shown potent inhibition against various multidrug-resistant strains of S. aureus, including VRSA with MICs in the range of 0.5–16 µg/mL. Interestingly, compound 17b showed potent antimycobacterial activity against M. tuberculosis H37Rv with MIC 1 µg/mL and a favorable selectivity index. It also exhibited potent inhibitory activity against DR-Mtb with MIC 1 µg/mL. Topoisomerase enzyme inhibition assay was carried out to validate the mechanism of action. Furthermore, in silico studies were performed to investigate the binding mode and interactions at the active site of the target enzyme. These results highlight the potential of naphthalimide-coumarin hybrids as novel antimicrobial agents.

Targeted synthesis via the structure-activity relationship: Biological evaluation of new 1,2,3-triazoles monoterpene as antitumor agents

A novel series of thiazolidinone based 1,2,3-triazole derivatives were designed, synthesized, and evaluated for their cytotoxic activity against four human cancer cell lines, including fibrosarcoma (HT-1080), lung carcinoma (A-549), and breast carcinoma (MCF-7 and MDA-MB-231). NMR (1H and 13C) and HRMS established the newly synthesized compounds' structural identification and molecular weight. Most synthesized compounds displayed moderate cytotoxic activity, with IC50 values from 20 to 40 μM. Furthermore, hybrid compounds 14b and 14d showed important inhibitory activity against HT-1080 and A-549 cancer cell lines with an IC50 value of 18 μM. Molecular docking analyses also confirmed a higher binding affinity of compounds 14a-e, as compared to Doxorubicin (control), towards Bcl-2 protein. In particular, compounds 14b and 14d had higher affinity for Bcl-2 as compared to other compounds.

Morphing cholinesterase inhibitor amiridine into multipotent drugs for the treatment of Alzheimer's disease

The search for novel drugs to address the medical needs of Alzheimer's disease (AD) is an ongoing process relying on the discovery of disease-modifying agents. Given the complexity of the disease, such an aim can be pursued by developing so-called multi-target directed ligands (MTDLs) that will impact the disease pathophysiology more comprehensively. Herewith, we contemplated the therapeutic efficacy of an amiridine drug acting as a cholinesterase inhibitor by converting it into a novel class of novel MTDLs. Applying the linking approach, we have paired amiridine as a core building block with memantine/adamantylamine, trolox, and substituted benzothiazole moieties to generate novel MTDLs endowed with additional properties like N-methyl-d-aspartate (NMDA) receptor affinity, antioxidant capacity, and anti-amyloid properties, respectively. The top-ranked amiridine-based compound 5d was also inspected by in silico to reveal the butyrylcholinesterase binding differences with its close structural analogue 5b. Our study provides insight into the discovery of novel amiridine-based drugs by broadening their target-engaged profile from cholinesterase inhibitors towards MTDLs with potential implications in AD therapy.

Discovery of novel benzimidazole derivatives as potent HDACs inhibitors against leukemia with (Thio)Hydantoin as zinc-binding moiety: Design, synthesis, enzyme inhibition, and cellular mechanistic study

Based on the well-established pharmacophoric features required for histone deacetylase (HDAC) inhibition, a novel series of easy-to-synthesize benzimidazole-linked (thio)hydantoin derivatives was designed and synthesized as HDAC6 inhibitors. All target compounds potently inhibited HDAC6 at nanomolar levels with compounds 2c, 2d, 4b and 4c (IC50s = 51.84–74.36 nM) being more potent than SAHA reference drug (IC50 = 91.73 nM). Additionally, the most potent derivatives were further assessed for their in vitro cytotoxic activity against two human leukemia cells. Hydantoin derivative 4c was equipotent/superior to SAHA against MOLT-4/CCRF-CEM leukemia cells, respectively and demonstrated safety profile better than that of SAHA against non-cancerous human cells. 4c was also screened against different HDAC isoforms. 4c was superior to SAHA against HDAC1. Cell-based assessment of 4c revealed a significant cell cycle arrest and apoptosis induction. Moreover, western blotting analysis showed increased levels of acetylated histone H3, histone H4 and α-tubulin in CCRF-CEM cells. Furthermore, docking study exposed the ability of title compounds to chelate Zn2+ located within HDAC6 active site. As well, in-silico evaluation of physicochemical properties showed that target compounds are promising candidates in terms of pharmacokinetic aspects.