Compounds 4d Research Articles

Exploring antitumor activity of novel imidazo[2,1-b]thiazole and imidazo[1,2-a]pyridine derivatives on MDA-231 cell line: targeting VEGFR-2 enzyme with computational insight

Our study explored the anticancer potential of novel heterocyclic compounds, specifically 6a-d, 8a-d, 12a-d, and 13a-d, which are derived from imidazo[2,1-b]thiazole and imidazo[1,2-a]pyridine and linked through a hydrazide moiety. These compounds were assessed for their anticancer activity toward the MDA-MB-231 breast cancer cell line to evaluate their effectiveness in inhibiting cancer cell proliferation. Among the compounds tested, 13c and 13d emerged as the most active, with IC50 values of 4.40 ± 2.87 µM and 4.69 ± 2.55 µM, respectively. These two compounds were further investigated for their effects on VEGFR-2 enzymatic activity, cell cycle progression, and apoptosis, then 13c and 13d were further evaluated for their impact on DNA fragmentation using the comet assay. Both compounds demonstrated a significant increase in DNA fragmentation, with levels of damage being twice as high as those observed in the untreated control cells. Molecular docking studies through VEGFR-2 demonstrated that compounds 13c and 13d bind to VEGFR-2 in a manner comparable to the co-crystallized ligand sunitinib I. Further analysis using density functional theory highlighted their favorable physical properties. Additionally, computational evaluations of ADME and drug-likeness suggest that these derivatives hold promise and merit further investigation. The ultimate goal is to develop effective, safe, and orally bioavailable VEGFR-2 inhibitors for potential use in anticancer therapy.

Design, Synthesis, and Evaluation of Novel Thiazole-Containing Algicides Inspired by Bacillamide A

The pursuit of highly effective, low-toxicity, and eco-friendly algicides for controlling and eradicating harmful algal blooms (HABs) is of paramount importance. The natural allelochemical bacillamide A has displayed impressive algicidal activity against harmful algae with favorable safety profiles. However, the poor synthetic efficiency and large dose requirements of bacillamide A limit its further application. In this paper, 17 thiazole-containing bacillamide derivatives (BDs) were designed and synthesized in three linear steps as potential algicides. Eight compounds (6a, 6c, 6j, 7b, 7c, 7d, 7e, and 7g) displayed potent inhibitory effects against Prorocentrum minimum, Skeletonema costatum, and Alexandrium pacificum, and they had similar or better activity than the positive control (CuSO4) and bacillamide A. Compound 6a exhibited the most potent algicidal activity against S. costatum (half-maximal effective concentration [EC50] = 0.11 μg/mL), being 23-fold more potent than bacillamide A, 28-fold more potent than CuSO4, and 39-fold more potent than Diuron. Compound 6j exhibited significant algicidal activity against the toxic dinoflagellates P. minimum (EC50 = 1.0 μg/mL) and A. pacificum (EC50 = 0.47 μg/mL), being 3–5-fold more potent than natural bacillamide A, Diuron, and CuSO4. Micrographs and SEM images revealed that 6j induced cell wall rupture and cellular content leakage. Biochemical and physiological studies indicated that 6j might partially disrupt the antioxidant and photosynthetic systems in algal cells, resulting in morphological changes, cell wall rupture, and inclusion leakage. Our work suggests that 6j has a distinct mode of action from CuSO4 and provides a promising candidate for the development of new algicides, worthy of further investigation.

Synthesis, spectroscopic, computational, topology, and molecular docking studies on N,N'-(4-methyl-1,3-phenylene)bis(1-(2,4-dichlorophenyl)methanimine)

The study extensively examined N,N'-(4-methyl-1,3-phenylene)bis(1-(2,4-dichlorophenyl)methanimine) (6D). Advanced spectroscopic techniques, including IR, Raman, NMR, and UV-VIS spectroscopies, were employed to analyse the molecule. The Schiff base was ultimately confirmed using NMR spectrum analysis. The UV-VIS study revealed a notable bathochromic change in the compound, indicating their electronic transitions. By using the HOMO–LUMO bond gap the titled compound reactivity sites were identified. The compound 6D HOMO–LUMO band gap is 3.70 eV. Various wave function investigations like MESP, HOMO–LUMO, RDG, ELF, LOL, and ALIE were conducted to elucidate the distribution of electronic charge, providing valuable insights into the behaviour of molecules. The biological probability of the synthesised compound was extensively assessed using a docking study. Using MEP and HOMO–LUMO investigations, we confirm nucleophilic and electrophilic attacking sites. In the docking study, the protein Bovine cytochrome bc1 complex stigma Tellin bound (PDB ID–1PP9) was downloaded. The docking study identified the most stable minimum binding energy is –6.26 kcal/mol.

Synthesis and Docking Studies of Novel Spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4-dione Derivatives

In this study, a set of spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4-dione derivatives 3a–p were synthesized starting from unsubstituted and N-methyl-substituted diendo- and diexo-2-aminonorbornene carboxamides, as well as various substituted isatins. The typical method involves a condensation reaction of alicyclic aminocarboxamide and isatin in the presence of a catalyst, using a solvent and an acceptable temperature. We developed a cost-effective and ecologically benign high-speed ball milling (HSBM), microwave irradiation (MW), and continuous flow (CF) technique to synthesize spiroquinazolinone molecule 3a. The structures of the synthesized compounds 3a–p were determined using 1D and 2D NMR spectroscopies. Furthermore, docking studies and absorption, distribution, metabolism, and toxicity (ADMET) predictions were used in this work. In agreement with the corresponding features found in the case of both the SARS-CoV-2 main protease (RCSB Protein Data Bank: 6LU7) and human mast cell tryptase (RCSB Protein Data Bank: 2ZA5) based on the estimated total energy and binding affinity, H bonds, and hydrophobicity in silico, compound 3d among our 3a–g, 3i–k, and 3m derivatives was found to be our top-rated compound.

Green Construction of Novel 3‐(Benzo[d][1,3]dioxol‐5‐yl)‐1,8‐naphthyridin‐2‐yl)amino)quinazoline‐2,4(1H,3H)‐dione and Phenyl‐[1,2,4]triazolo[4,3‐a][1,8]naphthyridine and Their Antimicrobial Activity

ABSTRACTA straightforward and an efficient green synthetic method has been outlined for the construction of 3‐(benzo[d][1, 3] dioxol‐5‐yl)‐1,8‐naphthyridine derivatives in the presence of glacial acetic acid and Cu(OAc)2 catalyst accomplished excellent yields in short reaction time. The reaction proceeds efficiently by using a greener way under microwave conditions to elevate the quantity of pure products. The purity of all the synthesized compounds was confirmed by IR, 1H and 13CNMR, LC–MS data and also from the elemental analyses studies. The synthesized compounds 7d and 7f performed strongest antibacterial activity against pathogenic cell lines Bacillus subtilis (17.5, 20.5 mm), Escherichia coli (28.5, 30 mm), and antifungal cell lines Candida albicans (18, 22.5 mm), and Aspergillus Niger (28.5, 40.5 mm) which are compared with clinical drugs Penicillin, Grieseofulvin. We scrutinized the remaining molecules and found that their activity ranged from modest to exceptional.

Design, synthesis and antifungal activity of arylhydrazine analogs containing diphenyl ether fragments.

Succinate dehydrogenase (SDH) represents a critical target in the development of novel fungicides. To address the growing issue of resistance and safeguard the economic viability of agricultural production, the pursuit of new succinate dehydrogenase inhibitors (SDHIs) has emerged as a significant focus of contemporary research. In this project, 32 arylhydrazine derivatives containing diphenyl ether structural units were synthesized and evaluated for their fungicidal activities against Rhizoctonia solani, Sclerotinia sclerotiorum, Alternaria alternata, Gibberella zeae, Alternaria solani and Colletotrichum gloeosporioides. In an in vitro fungicidal activity assay, compound D6 showed significant inhibitory activity against R. solani with a half-maximum effective concentration (EC50) of 0.09 mg L-1. The in vivo fungicidal activity demonstrated that compound D6 inhibited R. solani by 95.39% in rice leaves, which was significantly better than that of boscalid (85.76%). The results of SDH enzyme assay, molecular docking simulation, mitochondrial membrane potential assay, cytoplasmic release studies and morphological observations demonstrated that the target compound D6 not only had significant SDH inhibitory activity, but also affected the membrane integrity of mycelium. Bioactivity screening and validation of the mechanism of action indicated that compound D6 was a potentially unique SDHI, acting on SDH while also affecting cell membrane permeability, which deserved further study. © 2024 Society of Chemical Industry.

Semi-Preparation and X-ray Single-Crystal Structures of Sophocarpine-Based Isoxazoline Derivatives and Their Pesticidal Effects and Toxicology Study.

Recently, research and development of novel pesticides from natural plant products have received much attention. To accelerate the application of sophocarpine as the agrochemical candidate, a series of novel sophocarpine-based isoxazoline derivatives were prepared by the 1,3-dipolar [2 + 3] cycloaddition reaction of sophocarpine with different chloroximes. Their structures were well characterized by high-resolution mass spectra, infrared spectra, and proton/carbon-13 nuclear magnetic resonance spectra. Eight steric configurations of compounds 5a, 5e', 5f, 5g, 5h, 5i, 5r, and 5u' were further determined by X-ray single-crystallography. Against Aphis citricola Van der Goot, compounds 5n (LD50: 0.032 μg/nymph) and 5o (LD50: 0.024 μg/nymph) exhibited greater than 3.7- and 4.9-fold potent aphicidal activity compared to sophocarpine (LD50: 0.118 μg/nymph). Against Tetranychus cinnabarinus Boisduval, derivative 5g displayed the most promising acaricidal activity with the LC50 value of 0.247 mg/mL, which was 14.2-fold that of sophocarpine. Compounds 5d and 5g also exhibited good control efficacy against T. cinnabarinus. Scanning electron microscopy images indicated that compound 5g can destroy the mite cuticle layer. These results will provide the foundation for the structural modification and use of sophocarpine derivatives as agrochemicals in the future.

Synthesis and Cytotoxicity of Novel β-Ala-Phthalazine-Based Derivatives as VEGFR2 Inhibitors and Apoptosis-Inducers Against Liver Cancer

Some novel β-Ala-phthalazine derivatives were synthesized from the parent methyl 3-(2-(4-benzyl-1-oxophthalazin-2(1H)-yl) acetamido)propanoate (1). Then, ester 1 underwent hydrazinolysis to produce the hydrazide 2-(4-benzyl-1-oxophthalazin-2(1H)-yl)-N-(3-hydrazineyl-3-oxo propyl) acetamide (2). Under the azide coupling technique, hydrazide 2 formed azide 3 which was further coupled with some amines and amino acid esters hydrochloride to produce the corresponding novel dipeptides 4a–h and 5a–d, respectively. Finally, hydrazide 2 was condensed and/or cyclized with some ketones and/or active methylene compounds resulting in the formation of various derivatives 6a-e. Compounds 2, 6c, and 6d demonstrated significant cytotoxicity, with IC50 values of 1.33, 0.41, and 0.38 μM compared to Sorafenib (IC50 = 2.93 μM). Compounds 6d exhibited potent VEGFR2 inhibition by 97.6% with an IC50 value of 21.9 μM compared to Sorafenib (94.7% and IC50 value of 30.1 μM). The 6d treatment significantly increased apoptotic activity by 23.6-fold, causing a halt in cell proliferation at the G2/M phase. Ultimately, it exhibited a strong affinity for the VEGFR2 protein, with a binding energy of −26.8 Kcal/mol, and it established binding contacts with the crucial amino acids involved in the interaction.

In-vitro and in-silico studies based discovery of 2-aryl-N-(4-morpholinophenyl)thiazol-4-amines as promising DNA gyrase inhibitors

Background: DNA gyrase is an important enzyme for the survival of bacteria. Many DNA gyrase inhibitors are in clinical practice. However, these inhibitors also encompass certain toxic and drug/food interactions. This warrants the development of a new template as DNA gyrase inhibitors. Therefore, this study aimed to deliver morpholine-based thiazoles (5a-5l) as safer DNA gyrase inhibitors.Methods: The 5a-5l were prepared by reacting compound 3 with various aryl thioamides. The structures of 5a-5l were ascertained by their spectral records. The 5a-5l were subjected to their antibacterial activity potential (serial plate dilution method), DNA gyrase inhibiting activity, and toxicity analysis (MTT assay) against HepG2 & Vero cell lines. The in-silico studies (pharmacokinetic parameters and molecular docking) of 5a-5l were likewise performed.Results: It was surprisingly observed that the MIC values of 5a-5l were equal to the MIC values of ciprofloxacin (12.5 µg/ml) against the tested bacteria, whereas the DNA gyrase inhibitory activity (IC50 in µg/ml) of 5h (3.52), 5g (3.76), 5f (3.88), 5e (4.08), 5l (4.11), 5b (4.28), 5k (4.28), 5i (4.30), and 5d (4.32) was equal/better than ciprofloxacin (4.32). The MTT assay also implied the non-cytotoxic nature of 5a-5l against HepG2 & Vero cell lines up to 200 µg/ml concentration. The docking outcomes indicated a similar binding pattern of 5a-5l and ciprofloxacin at the active site of DNA gyrase, wherein 5a-5l displayed a better binding affinity for the active site. The in-silico toxicity data employing the ProTox-II web server indicated no hepatotoxicity, carcinogenicity, immunotoxicity, mutagenicity, or cytotoxic effect of 5a-5l. Also, the SwissADME software supported the drug-likeliness properties and high gastrointestinal absorption of 5a-5l.Conclusion: Compounds 5h, 5g, 5f, 5e, 5l, 5b, 5k, 5i, and 5d are potent DNA gyrase inhibitors with promising safety profiles.Keywords: Discovery; Morpholine; Thiazole; DNA gyrase; MTT assay; Docking

Pyrimidine appended heterocycles: synthesis, characterization, and biological evaluation

A new class of pyrimidine-based heterocycles has been successfully synthesized via a simple and efficient way starting from 2-keto-thiophene (1). The α,β-unsaturated ketone (chalcone) (3) was first synthesized by treating the ketone (1) with 4-methoxy benzaldehyde (2), followed by treating with amino formamidine hydrochloride to afford the intermediate pyrimidine moiety (4) which was converted to amide functionalized pyrimidines (5a–e), pyrimidine-2-imines (6a–e) and thiophene tethered pyrimidine-imidazoles (7a–e). The structures assigned to the new compounds are confirmed by IR, NMR, and MS studies. The newly synthesized compounds were subjected to a molecular docking study with the protein of Staphylococcus aureus (PDB ID: 1JIJ), for antioxidant and antibacterial activity. The compounds 5a, 6a, 6b, and 7d were found to show hydrogen bond interaction with active site amino acid residues with the binding energy of −8,08, −8.39, −8.64, and −8.02 kJ/mol, respectively, and may act as potential inhibitors of bacterial tyrosyl-tRNA synthetases. The biological study envisioned that the synthesized compound 7b has shown potent antioxidant properties with 74.07% scavenging activity at 400 µg/mL and compound 6b was found to exhibit excellent antibacterial activity with 16, 20, 21, and 22 mm zone of inhibition against S. aureus, Escherichia coli, Salmonella paratyphi-A and Bacillus subtilis bacterial strains, respectively.

Synthesis and characterization of novel dithiocarbamic thioanhydrides and their application for plant growth stimulant and phytotoxic activity

In this study, nineteen thioanhydrides were synthesized from the S-acylation reaction of sodium dithiocarbamates with various acyl chlorides in chloroform at room temperature. The synthesized thioanhydrides were evaluated for their growth-stimulating and phytotoxic activities. Benzoic (1a), 4-methoxy- (1b), 4-chloro- (1c), 2-bromo- (1e), 4-fluoro- (1f.) and 4-nitrobenzoic 1H-1,2,4-triazole-1-carbothioic thioanhydrides (1 g) showed moderate to excellent growth-stimulating activity, along with this (1c) exhibited excellent phytotoxic activity, 2,4-dichlorobenzoic 1H-1,2,4-triazole-1-carbothioic thioanhydride (1d) and 2,4-dichlorobenzoic pyrrolidine-1-carbothioic thioanhydride (2b) demonstrated inhibiting and moderate phytotoxic activities. Thioanhydrides (1a-c, 1f., 1 g) exhibited excellent germination energy and germination capacity of wheat seeds: 1a 82 and 90%, 1c 80 and 84%, 1 g 82 and 90% (0.01 mg/ml); 1b, 1 g 78 and 94%, 1c 78 and 90%, 1f. 80 and 94% (0.1 mg/ml). Thioanhydride (1e) showed moderate activity, germination energy and germination capacity were 72 and 76% (0.1 mg/ml), 78 and 84% (0.01 mg/ml). Thioanhydride (1d) demonstrated activity as a growth inhibitor with germination energy, and germination capacity 54 and 58% (0.1 mg/ml), 44 and 42% (0.01 mg/ml). Thioanhydride (1c) exhibited excellent phytotoxic activity analogically to herbicide 2,4-D only on lettuce seeds. Compounds (1d and 2b) were moderately active, inhibiting the growth of lettuce and bent grass seedlings.

Synthesis, Biological Evaluation, andMolecular Docking Studies of Indole-Based Heterocyclic Scaffolds as Potential Antibacterial Agents.

This study aimed to synthesize C3-indole derivatives linked to various heterocyclic scaffolds, including thiophenes, thiazolidine-4-ones, and 1,3,4-thiadiazoles, via the reaction of ethylthioacetanilide 2 with different α-haloketones.The structures of the target compounds were established using 1H and 13C nuclear magnetic resonance spectroscopy, mass spectrometry, infrared spectroscopy, and elemental analysis. The synthesized compounds were tested for antimicrobial activity against different microbes: S. aureus ATCC 6538 (Gram-positive bacteria), E. coli ATCC 25933 (Gram-negative bacteria), C. albicans ATCC 10231 (yeast), and fungi (A. niger NRRL-A326). Thiophene 6a, thiazolidine-4-one 8, and compound 10d exhibited the highest antimicrobial activities. The molecular docking study showed that compounds 2, 4, 6a, and 6c had good binding energy and favorable binding modes of interactions with the DNA gyrase B enzymes (PDB: 3U2D) and (PDB: 1S14). The results showed that the NH group of the indole in compounds 2 and 4, together with the nitrile group (CN), played an important role in inhibiting DNA gyrase B of S. aureus, PDB: 3U2D. Furthermore, the NH of the indole ring, together with the ethylamino group of compound 2, was crucial in inhibiting DNA gyrase B of E. coli, PDB: 1S14. These results could inspire further development of indole derivatives as antimicrobial drugs.

Pharmacophore‐Based Modeling, Synthesis, and Biological Evaluation of Novel Quinazoline/Quinoline Derivatives: Discovery of EGFR Inhibitors with Low Nanomolar Activity

AbstractThe main aim of this study is to obtain novel molecules that are more selective on cancer cells compared to healthy cells. For this purpose, four hit molecules are identified using 11 new pharmacophore hypotheses followed by scanning the in‐house database. Then, based on those hit molecules, the synthesis and analysis of four different series (three quinazolines and one quinoline series) are carried out, and their anticancer activity is investigated. Finally, by using molecular docking and dynamics simulation methods, binding mode and structure–activity relationship are examined. Among the quinazolin‐4(3H)‐one derivatives, those containing halogen atom are found to be potentially effective, while the best epidermal growth factor receptor (EGFR) inhibition and apoptosis induction are displayed by compounds containing 4‐amino‐1,2,4‐triazole moiety. Notably, four compounds (4h, 8d, 8l, and 8m) show EGFR inhibition activity at 5.298 ± 0.164, 5.46 ± 0.221, 2.670 ± 0.124, and 2.191 ± 0.908 × 10−9 m, their inhibitory activity is similar to or stronger than gefitinib (IC50: 4.169 ± 0.156 × 10−9 m). In addition, EGFR inhibitor concentration of 4g, 8e, and 8o is determined as 27588 ± 6.945, 52.41 ± 2.312, and 33657 ± 8.512 × 10−9 m. These findings indicate that generated pharmacophore hypotheses successfully determine new EGFR inhibitors. In conclusion, four novel compounds, more active than gefitinib with fewer side effects, are reached, and the structure–activity relationships are clarified.

Synthesis and biological evaluation of 1, 2, 3-triazole incorporated pyrrole derivatives as anticancer agents

A new series of 1,2,3-triazole skeleton incorporated pyrrole derivatives (11a–j) were developed and their chemical structures were confirmed by analytical data. Further, the anticancer profile of these newly derived compounds 11a–j was assessed against four types of human cancer cell lines such as human breast cancer (MCF-7), lung cancer (A549), colon cancer (Colo-205) and ovarian cancer (A2780) by employing of the MTT method and was compared with etoposide used as a positive control. Most of the examined derivatives displayed moderate to good activity compared with the positive control. Among them, five compounds 11a, 11b, 11c, 11d, and 11e showed more potent activity. Particularly, compound 11a showed superior activity.

Acetic acid-driven one-pot synthesis of 4,7-dihydro-[1,2,3]thiadiazolo[5,4-b]pyridine-6-carboxamides and Pharmacological Evaluations.

A diverse set of 4,7-dihydro-[1,2,3]thiadiazolo[5,4-b]pyridine-6-carboxamides 4(a-o) were synthesized via a one-pot reaction of 5-amino[1,2,3]thiadiazole, various aromatic aldehydes, and different acetoacetanilides, using glacial acetic acid as the solvent and without the need for any catalysts. The resulting compounds were obtained in moderate to good yields. All the newly synthesized compounds were evaluated for their antimicrobial activity. Among them, compound 4e demonstrated superior efficacy against Salinivibrio proteolyticus strain of Gram-(-Ve)-bacteria compared to ciprofloxacin. Compound 4d exhibited the highest potency against the fungal strain Candida albicans surpassing Amphotericin B. 4d and 4e's physicochemical characteristics were assessed. According to docking analysis, DHTDAPy 4e shows the higher binding affinity of -7.2 kcal moL-1 in the binding cavity of the receptor. These findings illustrate the safety and tolerability as well as the potency of newly syntehsized DHTDAPy against the fungal and bacterial infections.

Molecular docking, synthesis and preliminary evaluation of hybrid molecules of benzothiazole cross-linked with hydroxamic acid by certain linkers as HDAC inhibitors

Background Molecular hybridization in drug design is proved to be very successful approach to provide new chemical entities with potential activities and desirable physicochemical properties. Histone deacetylases (HDACs) are involved in controlling the behavior and acetylation of histone and non-histone proteins and their inhibition causes block of cell growth, differentiation, changes in gene expression, and death. Consequently, HDAC inhibitors may lead to anticytotoxic activity. An approach of synthesizing hybrid molecules of benzothiazole cross-linked with hydroxamic acid via an amino acid or aminoalkanoic acid was considered. This approach is expected to optimize the anticytotoxic activity of the proposed compounds. Methods Hybrid molecules of benzothiazole cross-linked with hydroxamic acid (2A-E) were synthesized and their chemical structures were confirmed by spectral analyses (FT-IR, 1H-NMR and 13C-NMR). These were subjected to molecular docking on HDAC8 (PDB ID: 1T69). Computational methods were employed using the SwissADME server to predict the ADME parameters and other physicochemical properties. The cytotoxicity evaluation was performed using MTT colorimetric assay. Results Hybrids (2A-E) recorded lower ΔG (-6.322 to - 9.46) than Vorinostat (SAHA, -5.375). ΔG is an affinity scoring function (kcal/mol) and is employed to rank the candidate poses as the sum of the electrostatic and Van der Waals energies. Benzothiazole cross-linked with hydroxamic acid by a p-aminobenzoic acid (2E) has recorded the lowest docking score of -9.460 and this may refer to the possibility of high inhibitory activity. The hybrids showed no violation from Lipinski’s rule and complied with parameters with low possible passive oral absorption and no penetration into BBB. Hybrid molecules of benzothiazole recorded very interesting results, particularly, 2D and 2E which showed significant and remarkable activity. Conclusions Hybrid molecules of benzothiazole cross-linked with hydroxamic acid recorded very interesting results, particularly, compounds 2D and 2E which showed significant and remarkable activity on lung cancer cell line type A549.

Benzimidazolium salts bearing ester group: Synthesis, characterization, crystal structure, molecular docking studies, and inhibitory properties against metabolic enzymes

In this work, the synthesis of several unsymmetrical benzimidazolium salts with an ester (2-ethoxy-2-oxoethyl) group on the nitrogen atom is described. The structures of all compounds were fully characterized by spectroscopic (1H, 13C NMR, FTIR) and analytical (elemental analysis) methods. However, single-crystal X-ray diffraction analysis elucidated the molecular and crystal structures of compounds 1a and 1c. Asymmetric units of both crystal structures contain two crystallographically independent molecules and two bromide anions. All compounds exhibited substantial inhibition against the cytosolic carbonic anhydrase isoforms (hCA I and hCA II) and acetylcholinesterase (AChE) with Ki values 51.00–45.18 nM, 46.94–305.65 nM, and 17.57–65.68 nM, respectively. Notably, compound 1d showed extreme inhibitory effect against hCA I with 51.00±5.31 nM (AZA: 275.44±13.32 nM), hCA II with 46.94±5.44 nM (AZA: 236.55±17.88 nM) and AChE with 17.57±3.14 nM (TAC: 80.44±6.88 nM). In silico approach showed that compound 1d could form stable complexes with target enzymes with a different binding affinity (BE:9.01 kcal/mol for AChE; -7.22 kcal/mol for hCA II and -6.51 kcal/mol for hCA I). The results supported the medical potential of benzimidazolium salts containing ester group. They significantly lighted our knowledge about the chemistry of side groups on phenyl ring especially in the para position as compared to ortho and meta positions.

Synthesis, cytotoxicity, docking, MD simulation, drug-likeness, ADMET prediction and multi spectroscopic studies of some novel quinoline-4-carboxamide derivatives as DNA intercalating and anticancer agents

In this study, some new quinoline-carboxamide derivatives possessing a flexible (dimethylamino) ethylcarboxamide side chain were synthesized as DNA intercalating agents. Synthesized compounds displayed potent cytotoxic activities against three human cancer cell lines including colorectal adenocarcinoma cancer cells (HT-29), breast cancer cells (MCF-7) and lung cancer cells (A549). Compound 3d showed promisingantiproliferative activity (IC50= 3.97 to 6.67 µM) against cancer cells. The simplest compound (compound 3a) without substitution displayed the weakest cytotoxic effects ranging from 24.6 to 42.3 μM. The interaction of the most cytotoxic compound 3d with calf thymus DNA (ctDNA) was evaluated by fluorescence, UV absorption, resonance light scattering (RLS), melting studies, viscosity measurements, circular dichroism (CD) spectroscopy, molecular docking and molecular dynamic (MD). Generally, studies displayed a combined quenching via intercalating binding mode of compound 3d to ctDNA.

Synthesis, spectroscopic characterization, DFT analysis, antibacterial, antifungal, antioxidant, molecular docking, and ADME study of 3,4-dihydro-2H-napthalen-1-one tagged chalcone derivatives

Chalcone derivatives were synthesized from 3,4-dihydro-2H-naphthalen-1-one using a base-catalyzed Claisen-Schmidt reaction and characterized by FT-IR, ¹H NMR, and ¹³C NMR spectroscopy. Density functional theory (DFT) with the B3LYP/6-311G(d,p) basis set was employed to explore the structural, electronic, and quantum properties of the compounds. Simulated electronic absorption spectra for compounds 3c and 3e in gas phase, DMSO, and DCM were generated using time-dependent DFT (TD-DFT). Compound 3c's first singlet excited state shifted from 376.10 nm in the gas phase to 390.08 nm in DMSO, while compound 3e shifted from 381.58 nm to 383.54 nm in DMSO. Experimental absorption values matched the theoretical predictions, with higher oscillator strengths in DMSO and DCM indicating solvent-enhanced transition probabilities. The antimicrobial activity of the chalcones was evaluated against four bacterial strains (E. coli, B. subtilis, S. aureus, and Streptococcus spp.) and four fungal strains (R. oryzae, P. chrysogenum, A. niger, and C. albicans). Compounds 3d and 3f showed strong antibacterial activity with MIC values of 3.9 µg/mL and moderate antifungal activity. Antioxidant properties were assessed using DPPH and hydroxyl radical assays, with compound 3d demonstrating 75.8 % and 76.4 % scavenging activity for OH and DPPH radicals, respectively. ADME studies were conducted to evaluate pharmacokinetics, and molecular docking studies revealed strong binding affinities. Compounds 3a and 3e had docking scores of -8.7 kcal/mol with the E. coli protein (PDB ID: 1KZN), while 3d and 3f performed best against B. subtilis (PDB ID: 1BAG) and S. aureus gyrase (PDB ID: 2XCT), with scores of -9.1 and -8.3 kcal/mol, respectively. Molecular dynamics simulation of compound 3d with 1BAG over 100 ns confirmed stable binding. These findings suggest chalcone derivatives have strong potential for pharmaceutical development.

3,8-Disubstituted Pyrazolo[1,5-a]quinazoline as GABAA Receptor Modulators: Synthesis, Electrophysiological Assays, and Molecular Modelling Studies

As a continuation of our study in the field of GABAA receptor modulators, we report the design and synthesis of new pyrazolo[1,5-a]quinazoline (PQ) bearing at the 8-position an oxygen or nitrogen function. All the final compounds and some intermediates, showing the three different forms of the pyrazolo[1,5-a]quinazoline scaffold (5-oxo-4,5-dihydro, -4,5-dihydro, and heteroaromatic form), have been screened with an electrophysiological technique on recombinant GABAAR (α1β2γ2-GABAAR), expressed in Xenopus laevis oocytes, by evaluating the variation in produced chlorine current, and permitting us to identify some interesting compounds (6d, 8a, 8b, and 14) on which further functional assays were performed. Molecular modelling studies (docking, minimization of complex ligand–receptor, and MD model) and a statistical analysis by a Hierarchical Cluster Analysis (HCA) have collocated these ligands in the class corresponding to their pharmacological profile. The HCA results are coherent with the model we recently published (Proximity Frequencies), identifying the residues γThr142 and αHis102 as discriminant for the agonist and antagonist profile.