Compounds 4h Research Articles

Design and Synthesis of Novel N-Benzylidene Derivatives of 3-Amino-4-imino-3,5-dihydro-4H-chromeno[2,3-d]pyrimidine under Microwave, In Silico ADME Predictions, In Vitro Antitumoral Activities and In Vivo Toxicity.

The synthesis of a series of new N-benzylidene derivatives of 3-amino-4-imino-3,5-dihydro-4H-chromeno[2,3-d]pyrimidine 10(a-l) bearing two points of molecular diversity is reported. These new compounds were synthesized in five steps including two steps under microwave dielectric heating. They were fully characterized using 1H and 13C NMR, FTIR and HRMS. The in silico physicochemical properties of compounds 10(a-l) were determined according to Lipinski's rules of five (RO5) associated with the prediction of their bioavailability. These new compounds 10(a-l) were tested for their antiproliferative activities in fibroblasts and eight representative human tumoral cell lines (Huh7 D12, Caco2, MDA-MB231, MDA-MB468, HCT116, PC3, MCF7 and PANC1). Among them, the compounds 10h and 10i showed sub-micromolar cytotoxic activity on tumor cell lines (0.23 < IC50 < 0.3 μM) and no toxicity on fibroblasts (IC50 > 25 μM). A dose-dependent inhibition of Store-Operated Ca+2 Entry (SOCE) was observed in the HEK293 cell line with 10h. In vitro embryotoxicity and angiogenesis on the mCherry transgenic zebrafish line showed that 10h presented no toxic effect and no angiogenic effect on embryos with a dose of 5 μM at 72 hpf.

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).

Synthesis, Characterization, Antimicrobial Activity, and Molecular Docking Study of Newer Chalcone-based Triazolo Pyrimidine Compounds

Abstract:: In this work, we present the synthesis of a newer series of 15 chalcone-based pyrimidine compounds 4a-o. All the compounds were characterized by elemental analysis, melting point determination, mass, FTIR, and NMR analysis. We have evaluated the antimicrobial activity of these compounds. The compounds showed good inhibition activity towards different bacterial and fungal species such as S. aureus, S. pneumonia, E. coli, P. aeruginosa, Candida albicans, Aspergillus niger, and Alternaria alternata. Compounds 4c, 4h, 4k, and 4g showed comparable activities to those of commercially available drugs. Molecular docking study showed good interaction between each of the compounds and DNA gyrase enzyme. The docking score of the compounds ranges between -8.0 to -8.9 kcal/mol. Further, the ADMET analysis indicated the potential of the compounds as a drug candidate.

PI3Kδ and mTOR dual inhibitors: Design, synthesis and anticancer evaluation of 3-substituted aminomethylquinoline analogues

Phosphatidylinositide-3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) have recently been identified as potential cancer targets. In our work, a new family of quinoline analogues was designed, developed, and evaluated as dual inhibitors of PI3Kδ/mTOR. The preliminary biological activity analysis led to the discovery of the lead compounds 5h and 5e. Compounds 5h and 5e exhibited excellent anti-tumor potency with IC50 of 0.26 µM and 0.34 µM against Ramos cells, respectively. Importantly, based on the enzymatic activity assay results, compounds 5h and 5e were identified as dual inhibitors of PI3Kδ and mTOR, with IC50 values of 0.042 µM and 0.056 µM for PI3Kδ and 0.059 µM and 0.073 µM for mTOR, respectively. Furthermore, these compounds showed superior selectivity for blocking PI3Kδ compared to other PI3K isoforms (α, β, and γ), supporting the concept of developing inhibitors that specifically target PI3Kδ/mTOR. The most effective compound 5h was chosen for additional biological testing. At a low dose of 0.5 µM, a western blot investigation confirmed the anticancer effects by inhibiting the PAM cascade, which in turn reduced downstream biomarkers pAkt (Ser473), pAkt (Thr308), and pRPS6 (Ser235/236). Furthermore, it increased apoptosis at the early (10.03 times) and late (17.95 times) stages in the Annexin-V assay as compared to the standard. In addition, the expression of p53, caspase-3, caspase-9, and the Bax/BCl-2 ratio were all significantly increased by compound 5h in the ELISA assay. Based on these results, it appears that 5h may activate the intrinsic apoptosis pathway, which in turn triggers cell death. Furthermore, the anticancer effects could be attributed to the inhibition of PI3Kδ/mTOR, as shown by docking interactions. Lastly, it demonstrated improved in vitro metabolic stability and passed the in silico ADMET/drug-likeness test. This profile recommends 5h for future in vivo PK-PD and efficacy investigations in animal cancer models.

New benzothiazole and benzoxazole picolinamide conjugates as potential anti-cancer agents: Design, synthesis, molecular docking and anticancer studies

An efficient synthesis was developed for the synthesis of N-(benzo[d]thiazol/oxazole-2-yl)-6-methyl-5-phenylpicolinamide derivatives(5a-5 h;8 compounds) with good yields by condensation reactions using benzo[d]thiazol/oxazole-2-amines with 5‑bromo-6‑methoxy picolinic acids in the presence of Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium (HATU)/ 4-Dimethylaminopyridine (DMAP) in Dimethylformamide (DMF) followed by coupling with phenylboronic acid in the presence of 1,1 -Bis(diphenylphosphino)ferrocene dichloropalladium(II):(Pd(dppf)Cl2·CH2Cl2), Cs2CO3 in Dioxane/H2O medium. Further, the anticancer potential of these derivatives was evaluated against DU-145(prostrate) and SKOV-3 (ovarian) cell lines. Results indicated moderate to good activity, with compound 5f exhibiting the best cytotoxicity with IC50 values of 8.3 and 8.9 µM for SKOV-3 and DU145 cells respectively as compared to standard Doxorubicin values 0.53 ± 0.08 and 0.68 ± 0.05 for same cell lines.. Additionally, molecular binding studies showed that compounds 5f and 5e had strong binding to human epidermal growth factor receptor, with binding energies of -8.5 and -8.2 Kcal/mol indicates conformational change in the structure of the receptor, leading to activation of signaling pathways promoting proliferation. So, the presence of electron rich OCH3 group on phenyl ring as well as thiazole ring in the designed molecule 5f makes it more potent to show strong cytotoxicity which was also revealed by its binding studies towards the human epidermal growth factor receptor. However, fluorine makes the compounds 5 g and 5 h to show moderate activity against these cancer cell lines.

Design and Synthesis of 2-Phenylindolizine Acetamides: Molecular Docking, in Vitro Antimicrobial and Anticancer Activity Evaluation.

In the present work, we synthesized a small library of 2-phenylindolizine acetamide derivatives 7a-i and studied their biological activity. The synthesis was accomplished starting with easily available starting material phenacyl bromide 1 proceeding through the key intermediate 6-methyl-7-nitro-2-phenylindolizine 4. All the compounds 7a-i were characterized using spectroscopy viz., 1H-NMR, 13C NMR, FTIR, and mass spectrometry. Interestingly, 2-phenylindolizine scaffolds 7c, 7f and 7g revealed a remarkable antibacterial activity against relevant organisms S. aureus, E. coli, S. pneumoniae, P. aeruginosa. The target compounds 7e and 7h showed excellent anticancer activity against Colo-205 and MDA-MB-231 cell lines with IC50 values of 68.62, 62.91, 54.23 and 46.34 μM respectively. Additionally, all the 2-phenylindolizine acetamide derivatives 7a-i were subjected to molecular docking prediction by Autodock 4.2. Compounds 7a, 7f and 7c exhibited very good hydrogen bonding amino acid interactions Asp83 (2.23 Å), Asp83 (2.08 Å), His74 (2.05 Å), His76 (1.71 Å), Ser80 (1.05 Å) with active site of Topoisomerase-IV from S. pneumoniae (4KPE). Further, the compounds 7a-i have revealed acceptable ranges for drug-likeliness properties upon evaluation using SwissADME for ADMET and physiochemical properties.

Indolyl imine compounds as multi-target agents; synthesis, antidiabetic, anticholinesterase, antioxidant activities and molecular modeling

A new range of indolyl imine system 3d-l has been successfully prepared from 4,6-dimethoxy-2,3-diphenyl-indole-7-carbaldehyde 2a and 4,6-dimethoxy-3-aryl-indole-7-carbaldehyde 2b-cvia Schiff base reaction. The structure of targeted compounds was confirmed by 1H and 13C NMR, FT-IR, mass spectrometry and single crystal X-ray diffraction techniques. The indolyl imine derivatives were also subjected to in vitro antidiabetic activities employing α-glucosidase and α-amylase enzymes. In terms of antidiabetic investigation, the α-glucosidase enzyme was found to be potential target due to the comparable inhibition concentrations with the standard acarbose and the compound 3e exhibited better potency than the standard. The anticholinesterase potency of the compounds was investigated towards the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The compounds displayed moderate efficiency against the BChE enzyme with the best inhibition concentration of 30.48 μM by the compound 3h. The antioxidant properties of final compounds were determined by DPPH radical scavenging, ABTS Cation Radical Decolarization and CUPRAC Cupric Reducing Antioxidant Capacity assay methods. The ABTS cation scavenging assay provided the best responses for the compounds and the candidates 3k and 3l were determined as promising targets for the antioxidant activity. Plausible binding mode and interaction of ligands with the selected enzyme have been studied by molecular docking, supporting the experimental results. In silico ADME showed high drug likeness of the synthesized compounds.

Structural, spectral and thermal characteristics of new tetrakis-complexes (NEt4)[LnL4] with dimethyl(4-chloro-3-nitrobenzoyl)amidophosphate

In continuation of the studies of new promising phosphors a new representative of carbacylamidophosphates (CAPhs) was synthesized and used as a ligand to obtain new lanthanides complexes (NEt4)[LnL4] (Ln = La, Y, Ce – Nd, Sm – Lu; L- = {C6H3(4-Cl-3-NO2) CONPO(OCH3)2}-). The structure of “free” ligand HL and complexes (NEt4)[YbL4] and (NEt4)[LuL4] were established by X-ray diffraction analysis. Dimethyl(4-chloro-3-nitrobenzoyl)amidophosphate has a dimeric structure. Dimers are formed by means of two hydrogen bonds of NH···OP type between two neighboring molecules. In the structure of the complexes the ligands are coordinated to the metal ion by the PO and CO groups of the chelate fragment forming six-membered not planar rings. In the crystal, the ligand and the complexes form numerous intermolecular contacts, including specific Cl···O intramolecular interaction. For the obtained compounds absorption, 1H NMR, and IR spectra were recorded and analyzed. Thermal gravimetric analysis and luminescence spectroscopy at 77 K and 298 K were used to characterize the obtained complexes.

Construction and Single-Crystal Structures of N-Isoxazolin-5-ylcarbonylindole Derivatives, and Their Pesticidal Activities and Toxicology Study.

To explore natural product-based pesticide candidates, a series of indole derivatives containing the isoxazoline skeleton at the N-1 position were synthesized by 1,3-dipolar [2 + 3] cycloaddition reaction. Their structures were characterized by melting points (mp), infrared (IR) spectra, proton nuclear magnetic resonance spectra (1H NMR), carbon-13 nuclear magnetic resonance spectra (13C NMR), and high resolution mass spectrometry (HRMS). The single-crystal structures of five compounds were presented. Against Tetranychus cinnabarinus Boisduval, compound 3b showed greater than 3.8-fold acaricidal activity of indole and good control effects under glasshouse conditions. Against Aphis citricola Van der Goot, compounds 3b and 3q exhibited 48.3- and 36.8-fold aphicidal activity of indole and 6-methylindole, respectively. Particularly, compound 3b showed good bioactivities against T. cinnabarinus and A. citricola. Against Eriosoma lanigerum Hausmann, compound 3h and 3i showed 2.1 and 1.9 times higher aphicidal activity compared to indole. Furthermore, the construction of the epidermal cuticle layer of 3b-treated carmine spider mites was distinctly damaged, which ultimately led to their death.

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.

Sulfonamide-incorporated bis(α-aminophosphonates) as promising carbonic anhydrase inhibitors: Design, synthesis, biological evaluation, and X-ray crystallographic studies.

A novel series of sulfonamide-incorporated bis(α-aminophosphonates) acting as effective carbonic anhydrase (CA, EC 4.2.1.1) inhibitors is reported. The synthesized bivalent ligands were tested against five human (h) isoforms, hCA I, hCA II, hCA VII, hCA IX, and hCA XIII. Such derivatives showed high activity and selectivity against the cancer-related, membrane-bound isoform hCA IX, and among them, compound 5h, tetraisopropyl (1,3-phenylenebis{[(4-sulfamoylphenyl)amino]methylene})bis(phosphonate)showed a KI of 15.1 nM, being highly selective against this isoform over all other investigated ones (hCA I/IX = 42; hCA II/IX = 6, hCA VII/IX = 3, hCA XIII/IX = 5). Therefore, compound 5h could be a potential lead for the development of selective anticancer agents. The newly developed sulfonamides were also found effective inhibitors against the cytosolic hCA XIII isoform. Compound 5i displayed the best inhibition against this isoform with a KI of 17.2 nM, equal to that of the well-known inhibitor acetazolamide (AAZ), but significantly more selective over all other tested isoforms (hCA I/XIII = 239; hCA II/XIII = 23, hCA VII/XIII = 2, hCA IX/XIII = 3) compared to AAZ.

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.

New imidazole-2-thiones linked to acenaphythylenone as dual DNA intercalators and topoisomerase II inhibitors: structural optimization, docking, and apoptosis studies

In this article, a new series of 2-((3,5-disubstituted-2-thioxo-imidazol-1-yl)imino)acenaphthylen-1(2H)-ones were synthesized. Imidazole-2-thione with acenaphthylen-one gave a hybrid scaffold that integrated key structural elements essential for DNA damage via direct DNA intercalation and inhibition of the topoisomerase II enzyme. All the synthesized compounds were screened to detect their DNA damage using a terbium fluorescent probe. Results demonstrated that 4-phenyl-imidazoles 5b and 5e in addition to 4-(4-chlorophenyl)imidazoles 5h and 5j would induce detectable potent damage in ctDNA. The four most potent compounds as DNA intercalators were further evaluated for their antiproliferative activity against HepG2, MCF-7 and HCT-116 utilizing the MTT assay. The highest anticancer activity was recorded with compounds 5b and 5h against the breast cancer cell line MCF-7 which were 1.5- and 3- folds more active than doxorubicin, respectively. Therefore, imidazole-2-thione tethered acenaphthylenone derivatives can be considered as promising scaffold for the development of effective dual DNA intercalators and topoisomerase II inhibitors.

Benzocoumarin‐Fused Triskelions Exhibit AIEE Due to Inhibited Molecular Inversion

AbstractDeveloping aggregation‐induced emission luminogens (AIEgens) is a unique strategy for alleviating concentration quenching of π‐conjugated organic compounds. This AIE behaviour can be induced not only in organic dyes with rotors but also in invertible π‐conjugated systems. Herein, intramolecular Ullmann coupling was used to synthesize π‐twisted triskelion‐shaped AIEgens (2F, 2G, and 2H), in which benzo[f], [g], and [h] coumarins were fused into the benzene core to form a helical propeller shape. These structural isomers had unique molecular thicknesses and planarities depending on the fusion mode of the benzocoumarin. The racemic crystals, PPP and MMM, had different overlapping molecular configurations because of their twisted molecular frameworks. Compounds 2F, 2G and 2H demonstrated weak fluorescence emission in diluted solutions resulting from molecular motions caused by the isomerization process during molecular inversion. By comparison, aggregates exhibited enhanced emission intensity. These π‐twisted triskelions exhibited the characteristics of AIEgens.

Synthesis and docking of new 4-(2-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)thiazol-2-amine derivatives as an antimicrobial agent

The novel series of 4-(2-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)thiazol-2-amine 5a-h have been synthesized by oxidation reaction of acetophenone tethered 1,4-disubstituted triazole derivatives with thiourea in the presence of iodine. All newly synthesized compounds were characterized by IR, 1H NMR, 13C NMR, HRMS, and elemental analysis techniques. The antibacterial activity of novel compounds were evaluated against S. aureus, P. aeruginosa, E. coli and S. pyogenes bacterial strains whereas antifungal activity were screened against A. niger, C. albicans and A. clavatus pathogen of fungi. The compounds 5a, 5b, 5f and 5h showed excellent antibacterial activity, whereas 5f and 5g showed excellent antifungal activity. This may be attributed due to the presence of 4-CH3, 3-F, 4-F and 4-CF3 functional groups in benzene ring. The all results were compared with standard Ampicillin and Griseofulvin antibacterial and antifungal drugs, respectively. The molecular docking studies of compounds were carried out to measure effective bindings and molecular interactions. The experimentally observed values of antifungal activity and binding affinities values of molecular docking showed good correlation.

Solvent-free strategy for facile synthesis and cytotoxicity evaluation of benzimidazole derivatives

This study reports a facile synthesis and the cytotoxic evaluation of N–H benzimidazoles. This synthetic method made use of the condensation reaction between o-phenylenediamine and benzylamine and was highlighted by its solvent-free reaction conditions and short reaction time with the use of Na2S2O5 as an inexpensive and environmentally friendly oxidizing agent. The cytotoxicity assays revealed that the benzimidazole derivatives 3l, 3h, and 3r displayed strong activity against the HeLa cancer cell line with the IC50 of 1.54 μM, 0.86 μM, and 1.03 μM, respectively, which were 5.6-fold, 10-fold, and 8-fold stronger than the positive control 5-fluorouracil (5-FU, IC50 = 8.61 μM). Furthermore, both compounds 3h and 3r exhibited similar cytotoxicities against MCF-7, which were equivalent to that of 5-FU and about 2.5-fold stronger than 5-FU towards the A549 cell line.

Synthesis of thiadiazole derivatives as competitive inhibitors of α-glucosidase and tyrosinase

A new series of thiadiazole derivatives (3a-3j) were designed and synthesized. Their structures were confirmed by spectral data and then subjected to in vitro assessment including α-glucosidase and tyrosinase inhibitory activities. The results of the inhibitory activity show that all the synthesized analogs effectively inhibit α-glucosidase and tyrosinase, with IC50 values ranging from 0.42± 0.011 to 1.83±0.076 µM for α-glucosidase and 0.97±0.025 to 3.87±0.141 µM for tyrosinase. There, compound 3e (IC50 = 0.42± 0.011 μM) exhibited the most effective anti-α-glucosidase activity, with a Ki value of 0.18 ± 0.006 μM. Furthermore, compound 3h (IC50 = 0.97±0.025 μM) showed the best tyrosinase inhibition activity with the value of Ki 0.41 ± 0.017 μM. Through the in silico molecular docking analysis, the ability of the synthesized analogs to inhibit α-glucosidase and tyrosinase was also examined. Molecular dynamics (MD) simulations and MM-GBSA calculations were performed for 3e and 3h to support our biological findings. The favorable binding affinities and interactions displayed by both compounds with the active sites of the target enzymes illuminate their potential as competitive inhibitors. The molecular dynamics results suggest insights into the system's dynamic behavior, including the ligand-receptor complex's stability and flexibility, conformational changes, and intermolecular interactions over time. As a result of this study, it was determined that the structure of the compounds is important in drug design for diabetes and dermatological disorders.

New Benzimidazole-Triazole Derivatives as Topoisomerase I Inhibitors: Design, Synthesis, Anticancer Screening, and Molecular Modeling Studies.

In this study, we designed, synthesized, and evaluated a series of 1,2,4-triazole benzimidazoles for their cytotoxic effects against the A549, C6, and NIH3T3 cell lines. Additionally, these compounds were assessed for their inhibitory activity against DNA topoisomerase I, aiming to develop novel anticancer agents. The synthesized final compounds 4a-h were characterized using 1H NMR, 13C NMR, and HRMS. Among them, compounds 4b and 4h emerged as the most potent agents against the A549 cell line, exhibiting an IC50 value of 7.34 ± 0.21 μM and 4.56 ± 0.18 μM, respectively. These results were compared to standard drugs, doxorubicin (IC50 = 12.420 ± 0.5 μM) and Hoechst 33342 (IC50 = 0.422 ± 0.02 μM). Notably, all tested compounds displayed higher cytotoxicity toward A549 cells than C6 cells. Compounds 4b and 4h demonstrated significant inhibitory activity against topoisomerase I, highlighting their potential as lead compounds in anticancer therapy. Subsequent in silico molecular docking studies were conducted to elucidate the potential binding interactions of compounds 4b and 4h with the target enzyme topoisomerase I. Molecular dynamics studies also assessed and validated the binding affinity and stability. These studies confirmed the promising binding affinity of these compounds, reinforcing their status as lead candidates. According to DFT, compound 4b having the lower energy gap value (ΔE = 3.598 eV) is more chemically reactive than the others, which is consistent with significant inhibitory activity against topoisomerase I. Furthermore, in silico ADME profiles for compounds 4b and 4h were evaluated using SwissADME, providing insights into their pharmacokinetic properties.

Discovery of a Potent and Cell-Active Inhibitor of DNA 6mA Demethylase ALKBH1.

N6-Methyladenine (6mA) of DNA has emerged as a novel epigenetic mark in eukaryotes, and several 6mA effector proteins have been identified. However, efforts to selectively inhibit the biological functions of these effector proteins with small molecules are unsuccessful to date. Here we report the first potent and selective small molecule inhibitor (13h) of AlkB homologue 1 (ALKBH1), the only validated 6mA demethylase. 13h showed an IC50 of 0.026 ± 0.013 μM and 1.39 ± 0.13 μM in the fluorescence polarization (FP) and enzyme activity assay, respectively, and a KD of 0.112 ± 0.017 μM in the isothermal titration calorimetry (ITC) assay. The potency of 13h was well explained by the cocrystal structure of the 13h-ALKBH1 complex. Furthermore, 13h displayed excellent selectivity for ALKBH1. In cells, compound 13h and its derivative 16 were able to engage ALKBH1 and modulate the 6mA levels. Collectively, our study identified the first potent, isoform selective, and cell-active ALKBH1 inhibitor, providing a tool compound for exploring the biological functions of ALKBH1 and DNA 6mA.