Compounds 4k Research Articles

Identification of New N-methyl-piperazine Chalcones as Dual MAO-B/AChE Inhibitors

Monoamine oxidase-B (MAO-B), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) have been considered target enzymes of depression and neurodegenerative diseases, including Alzheimer's disease (AD). In this study, seventeen N-methyl-piperazine chalcones were synthesized, and their inhibitory activities were evaluated against the target enzymes. Compound 2k (3-trifluoromethyl-4-fluorinated derivative) showed the highest selective inhibition against MAO-B with an IC50 of 0.71 μM and selectivity index (SI) of 56.34, followed by 2n (2-fluoro-5-bromophenyl derivative) (IC50 = 1.11 μM, SI = 16.04). Compounds 2k and 2n were reversible competitive MAO-B inhibitors with Ki values of 0.21 and 0.28 μM, respectively. Moreover, 2k and 2n effectively inhibited AChE with IC50 of 8.10 and 4.32 μM, which underscored their multi-target inhibitory modes. Interestingly, compound 2o elicited remarkable inhibitions over MAO-B, AChE, and BChE with IC50 of 1.19-3.87 μM. A cell-based assay of compounds 2k and 2n against Vero normal cells pointed out their low cytotoxicity. In a docking simulation, 2k showed the lowest energy for MAO-B (-11.6 kcal/mol) with four hydrogen bonds and two π-π interactions. Furthermore, in silico studies were conducted, and disclosed that 2k and 2n are expected to possess favorable pharmacokinetic properties, such as the ability to penetrate the blood-brain barrier (BBB). In view of these findings, compounds 2k and 2n could serve as promising potential candidates for the treatment of neurodegenerative diseases.

New imidazole derivatives as aromatase inhibitor: Design, synthesis, biological activity, molecular docking, and computational ADME-Tox studies

In this study, a series of imidazole derivatives was designed, synthesized, and evaluated for in vitro biological activity on the human breast cancer cell line MCF7 by MTT assay. To determine the selectivity of the compounds, their cytotoxic effects on the L929 (healthy mouse fibroblast) cell line were also investigated. Compounds 1a, 1b, and 1d were found to be more effective than the reference drug cisplatin against the MCF7 cell line. It is seen that the cytotoxic effects of the compounds on the L929 cell line are quite low, and the compounds are found to be highly selective. The inhibition potentials of the compounds 1a, 1b, 1d, and 1k which were effective on the MCF7 cell line, and on the aromatase enzyme were evaluated and it was found that the compounds had similar effects to the reference drug letrozole. Further, the interactions between the best active compounds and the human aromatase cytochrome P450 (CYP) enzyme were analyzed through a molecular docking study. The findings suggest that these compounds could be a promising candidate for the creation of a new family of non-steroidal aromatase inhibitors. Finally, computational ADME-Tox studies of compounds 1a, 1b, 1d, and 1k were performed and found to have the appropriate profile.

Synthesis of oxamide-hydrazone hybrid derivatives as potential anticancer agents.

Considering various studies implying anticancer activity of the hydrazone and oxamide derivatives through different mechanisms such as kinases and calpain inhibition, herein, we report the synthesis, characterization, and evaluation of the antiproliferative effect of a series of hydrazones bearing oxamide moiety compounds (7a-7n) against a panel of cancer cell lines to explore a novel and promising anticancer agent (7k). Chemical structures of the synthesized compounds were confirmed by FTIR, 1H-NMR, 13C-NMR, and mass spectra. The antiproliferative activity and cell cycle progression of the target compound were investigated using the MTT assay and flow cytometry. Compound 7k with 2-hydroxybenzylidene structure was found to have a significant in vitro anti-proliferative influence on MDA-MB-231 (human adenocarcinoma breast cancer) and 4T1 (mouse mammary tumor) cells as the model of triple-negative breast cancer, with the IC50-72h values of 7.73 ± 1.05 and 1.82 ± 1.14 μM, respectively. Following 72-h incubation with compound 7k, it caused MDA-MB-231 cell death through G1/S cell cycle arrest at high concentrations (12 and 16 μM). Conclusively, this study for the first time reports the anti-proliferative efficacy of compound 7k possessing 2-hydroxyphenyl moiety, which may serve as a potent candidate in triple-negative breast cancer treatment.

Synthesis and Phytotoxic Evaluation of 3-Indolylglycine Derivatives as New Natural-Like Herbicides

A novel class of potential herbicides, 3-indolylglycines were synthesized using an effective, green and rapid approach via multicomponent reaction (aza-Friedel-Crafts) between indoles, aldehydes and anilines in a water/sodium dodecyl sulfate system. The main advantages of this methodology are ease of handling, scalable to gram scale and a metal-free approach. The reaction is compatible with a variety of functional groups, obtaining the desired products in moderate to excellent yields. The biological activity of the 3-indolylglycines was evaluated, and it was found that these compounds interfere with the germination and radicle growth of Lactuca sativa, mainly the compound 4k.

Synthesis, characterization and biological evaluation of pyrazole-based benzene sulfonamides as inhibitors of human carbonic anhydrase II, IX and XII.

The aberrant level of the carbonic anhydrase isozymes is linked with various disorders which include glaucoma, epilepsy, altitude sickness and obesity. In the present study, a series of the pyrazole-based benzene sulfonamides derivatives (4a-4l) were designed, synthesized and evaluated as the inhibitors of the three isoforms of human carbonic anhydrases (hCAII, hCAIX and hCAXII). A number of the derivatives were found more active inhibitors than acetazolamide used as a standard against the human hCAII, hCAIX and hCAXII. Among the series, the compound 4k inhibited the hCAII to a submicromolar level presenting the IC50 ± SEM concentration of 0.24 ± 0.18 μM, the inhibitor 4j reduced the activity of the hCAIX to the IC50 ± SEM equals 0.15 ± 0.07 μM, whereas, the molecule 4g blocked the catalytic potential of the isozyme hCAXII with as low as IC50 concentration of 0.12 ± 0.07 μM. In addition, compounds 4e and 4k were screened as the preferential inhibitors of the isoform hCAXII as compared to the hCAIX and hCAXII with half of the maximal concentrations of 0.75 ± 0.13 μM, and 0.24 ± 0.18 μM, respectively. Moreover, the compounds 4k, 4j and 4g were docked inside the active pocket of the crystallographic structure of the isoforms hCAXII, hCAIX and hCAXII, respectively. The docked inhibitors showed the binding interactions with the important amino acid residues such as Leu1198, Thr1199, His1094, and Phe1131 in hCAXII isozyme; residues Val121, Thr200, Pro203, and Gln71 in hCAIX; the amino acids Val119, Leu197, Gln89, and Asn64 in the case of hCAXII. In addition, structural geometries, reactivity descriptors, optimization energy and electronic parameters were calculated to predict the activity of the synthesized compounds.

Design, synthesis, in silico, and in vitro evaluation of benzylbenzimidazolone derivatives as potential drugs on α-glucosidase and glucokinase as pharmacological targets.

Benzimidazolones have shown biological activities, including antihyperglycemic and hypoglycemic, by inhibiting or activating of α-glu and GK. The aim of this study is the rational design of compounds using in silico assays to delimitate the selection of structures to synthesize and the in vitro evaluation of benzimidazolone derivatives in blood glucose control. A docking of 23 benzimidazolone derivatives was performed; selecting the compounds with better in silico profiles to synthesize by microwave-irradiation/conventional heat and evaluate in enzymatic in vitro evaluation. Compounds 2k, 2m, 2r, and 2s presented the best in silico profiles, showing good affinity energy (-10.9 to -8.6 kcal mol-1) and binding with catalytic-amino acids. They were synthesized at 70 °C and 24 h using DMF as the solvent and potassium carbonate (yield: 22-38%). The results with α-glu showed moderate inhibition of 2k (14 ± 1.23-29 ± 0.45), 2m (12 ± 2.21-36 ± 0.30), 2r (7 ± 2.21-13 ± 1.34), and 2s (11 ± 0.74-35 ± 2.95) at evaluated concentrations (0.1 to 100 μg mL-1). The GK activation assay showed an enzymatic activity increase; compound 2k increased 1.31 and 2.83 more than normal activity, 2m (2.13-fold), 2s (2.86 and 3.74-fold) at 100 and 200 μg mL-1 respectively. The present study showed that the 2s derivative presents moderate potential as an α-glu inhibitor and a good activator potential of GK, suggesting that this compound is a good candidate for blood glucose control through antihyperglycemic and hypoglycemic mechanisms.

Antioxidant activity of novel 4H- chromene tethered 1,2,3-Triazole Analogues: Synthesis and molecular docking studies

Novel 4H chromene coupled triazole hybrids 8a-l were synthesized through a hassle free multicomponent one pot synthesis and click chemistry protocols. The structures of novel compounds were established by interpretation of 1H NMR, 13C NMR, IR and Mass spectral data. The novel hybrids were screened for their invitro antioxidant activity by employing DPPH and Hydrogen peroxide radical scavenging assays, using Ascorbic acid as standard reference. Novel compounds 8h and 8i exhibited superior radical quenching percentage with IC50 value of 1.29 ± 0.35 and 1.23 ± 0.34 µM respectively, compared to the IC50 value of (1.46 ± 0.52 µM)Ascorbic acid. Compounds 8f, 8j and 8k also demonstrated best IC50 value of 3.02 ± 0.62, 2.45 ± 0.53 and 3.18 ± 0.25 µM in comparison to reference. The molecular docking studies of target compounds against the crystal structure of NADPH oxidase endorsed best docking scores and binding interactions, and are in agreement to experimental data.

An efficient, catalyst-free and aqueous ethanol-mediated synthesis of 5-((2-aminothiazol-5-yl)(phenyl)methyl)-6-hydroxypyrimidine-2,4(1H,3H)-dione derivatives and their antioxidant activity.

In this study, we effectively developed a catalyst-free multicomponent synthesis of 5-((2-aminothiazol-5-yl)(phenyl)methyl)-6-hydroxypyrimidine-2,4(1H,3H)-dione derivatives employing 2-aminothiazole, N',N'-dimethyl barbituric acid/barbituric acid and different aldehydes at 80 °C in an aqueous ethanol medium (1 : 1) using group-assisted purification (GAP) chemistry. The essential characteristics of this methodology include superior green credential parameters, metal-free multicomponent synthesis, faster reaction times, greater product yields, simple product purification without column chromatography and higher product yields. All of the synthesized compounds were analyzed against the HepG2 cell line. Compounds 4j and 4k shows good anti-proliferative effects on HepG2 cells. Furthermore, the ABTS and DPPH scavenging assays were used to determine the antioxidant activity of all compounds (4a-r). In both ABTS and DPPH radical scavenging assays, compounds 4e, 4i, 4j, 4o and 4r exhibit excellent potency compared to the standard ascorbic acid.

Synthesis and biological evaluation of capsaicin analogues as antioxidant and neuroprotective agents.

Capsaicin and its analogues 3a-3q were designed and synthesized as potential new antioxidant and neuroprotective agents. Many analogues exhibited good antioxidant effects, and some showed more potent free radical scavenging activities than the positive drug quercetin (IC50 = 8.70 ± 1.75 μM for DPPH assay and 13.85 ± 2.87 μM for ABTS assay, respectively). The phenolic hydroxyl of capsaicin analogues was critical in determining antioxidant activity. Among these compounds, 3k displayed the most potent antioxidant activity. Cell vitality tests revealed that the representative compound 3k was good at protecting cells from H2O2-induced oxidative damage at low concentrations (cell viability increased to 90.0 ± 5.5% at 10 μM). In addition, the study demonstrated that 3k could reduce intracellular ROS accumulation and increase GSH levels to prevent H2O2-induced oxidative stress in SY5Y cells. In the mitochondrial membrane potential assay, 3k significantly increased the MMP level of SY5Y cells treated with H2O2 and played an anti-neuronal cell death role. These results provide a promising strategy to develop novel capsaicin analogues as potential antioxidant and neuroprotective agents.

Novel Specific Pyruvate Kinase M2 Inhibitor, Compound 3h, Induces Apoptosis and Autophagy through Suppressing Akt/mTOR Signaling Pathway in LNCaP Cells

Pyruvate kinase M2 (PKM2) is a key enzyme involved in the regulation of glycolysis. Although PKM2 is overexpressed in various tumor tissues, its functional role in cancer chemotherapy remains unexplored. In this study, we investigated the anticancer activity of a new PKM2 inhibitor, compound 3h, through the cell metabolism and associated signaling pathways in prostate cancer cells. To evaluate the molecular basis of specific PKM2 inhibitors, the interactions of compounds 3h and 3K with the PKM2 protein were assessed via molecular docking. We found that, compared to compound 3K, compound 3h exhibited a higher binding affinity for PKM2. Moreover, compound 3h significantly inhibited the pyruvate kinase activity and PKM2 expression. Cytotoxicity and colony formation assays revealed the potent anticancer activity of compound 3h against LNCaP cells. Compound 3h significantly increased the apoptotic and autophagic cell death in LNCaP cells. In addition, compound 3h induced AMPK activation along with the inhibition of the mTOR/p70S6K pathway. Furthermore, compound 3h significantly inhibited glycolysis and mitochondrial respiration, as determined by analyzing the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) production. Our results revealed that compound 3h caused apoptotic and autophagic cell death in LNCaP cells by inhibiting cancer cell metabolism. Therefore, blocking glycolytic pathways using specific PKM2 inhibitors can target cancer cell metabolism in PKM2-overexpressed prostate cancer cells.

Design, Synthesis, Inhibitory Activity, and Molecular Modeling of Novel Pyrazole-Furan/Thiophene Carboxamide Hybrids as Potential Fungicides Targeting Succinate Dehydrogenase

To discover new fungicides targeting succinate dehydrogenase (SDH), 36 new furan/thiophene carboxamides containing 4,5-dihydropyrazole rings were designed, synthesized, and characterized. The crystal structure of compound 5l was determined with the X-ray diffraction (XRD) of single crystals. The antifungal activity of these compounds was studied against Botrytis cinerea, Pyricularia oryzae, Erysiphe graminis, Physalospora piricola, and Penicillium digitatum. Bioassay results were that most compounds had obvious inhibitory activity at 20 μg/mL. Compounds 5j, 5k, and 5l possessed outstanding inhibitory activity against B. cinerea. Their EC50 values were 0.540, 0.676, and 0.392 μg/mL, respectively. They owned better effects than fluxapyroxad (EC50 = 0.791 μg/mL). In the meantime, the inhibitory activity of 16 compounds was evaluated against SDH. It turned out that these compounds displayed excellent activity. The IC50 values of compounds 5j, 5k, and 5l reached 0.738, 0.873, and 0.506 μg/mL, respectively, whereas the IC50 value of fluxapyroxad was 1.031 μg/mL. The results of molecular dynamics (MD) simulation showed that compound 5l possessed a stronger affinity to SDH than fluxapyroxad.

Repositioning of acefylline as anti-cancer drug: Synthesis, anticancer and computational studies of azomethines derived from acefylline tethered 4-amino-3-mercapto-1,2,4-triazole.

Novel azomethines derived from acefylline tethered triazole hybrids (7a-k) have been synthesized and evaluated against human liver cancer cell line (Hep G2) using MTT assay. The synthesized series of azomethines exhibited promising efficacy against liver cancer cell line. Screening of the synthesized series identified compound 7d with the least cell viability value (11.71 ± 0.39%) as the most potent anticancer agent in contrast to the reference drug acefylline (cell viability = 80 ± 3.87%). In this study, the potentials of the novel agents (7a-k) to inhibit liver cancer proteins were assessed. Subsequently, the structure-activity relationship of the potential drug candidates was assessed via ADME/T molecular screening. The cytotoxic potential of these derivatives was also investigated by hemolysis and thrombolysis. Their hemolytic and thrombolytic studies showed that all of these drugs had very low cytotoxicity and moderate clot lysis activity. Compound 7g (0.26% hemolysis) and 7k (52.1% clot lysis) were the least toxic and moderate thrombolytic agents respectively.

Anti-proliferative activities of 4H-pyran derivatives synthesized from benzoylacetone

ABSTRACT. Benzoylacetone (1) underwent a series of multi-component reactions with aromatic aldehydes and malononitrile or ethyl cyanoacetate to produce the pyran derivatives 4a-f. The latter compounds reacted with malononitrile or ethyl cyanoacetate to yield the condensation products 5a-m. On the other hand, the reaction of 4a-f with either the diazonium salts 6a-c yielded the arylhydrazone derivatives 7a-i. The multi-component reaction of (1) with aromatic adehydes and cyclohexan-1,3-dione produced the pyran derivatives 9a-c. Compound 1 underwent the Gewald’s reactions with elemental sulfur and malononitrile or ethyl cyanacetate yielding the thiophene derivatives 10a,b. Evaluations of the synthesized products were carried out against some selected cancer cell lines and the most active compounds were further evaluated against the seventeen cancer cell lines classified according to the disease. Morphological changes of A549 cell line by the effect of compound 7k was studied using microenvironment of the lung tissue where an excellent results was obtained.
 
 KEY WORDS: Benzoylacetone, Multi-component reactions, Pyran, Thiophene, Arylhydrazone, Cytotoxicity
 
 Bull. Chem. Soc. Ethiop. 2023, 37(2), 405-425. 
 DOI: https://dx.doi.org/10.4314/bcse.v37i2.12

Synthesis, anticancer evaluation, and molecular docking studies of thiazolyl-pyrazoline derivatives

The molecular hybridization of thiazole and pyrazoline heterocyclic structures with diverse activities appears to be an interesting strategy for developing new anticancer compounds. This study presents the synthesis of eleven new thiazolyl-pyrazoline derivatives (7a-k) and the evaluation of their in-vitro anti-proliferative activities against human lung carcinoma (A549) and human melanoma cancer (A375) cell lines through MTT assay. In comparison to the positive reference drug erlotinib (IC50 = 34.16 µM in A549 and IC50 = 25.85 µM in A375), four compounds (7e, 7h, 7j, and 7k) were identified as the most active against both cell lines (especially compound 7k with IC50 = 20.28 µM in A549 and 16.08 µM in A375). Additionally, these potent compounds were selected to be investigated for their anti-metastasis and anti-inflammatory properties via inhibition of the expression of matrix metalloproteinase 2, 9 (MMP-2, 9) and cyclooxygenase 2 (COX-2). In A549 cells, upon exposure to compounds 7e and 7j, COX-2 expression is decreased, whereas compounds 7e, 7j, and 7k reduced COX-2 expression in A375 cell lines. Molecular docking studies were carried out to show the possible interactions of synthesized compounds with the predicted active site of the COX-2 protein. The results revealed that compounds 7e and 7j can bind well to the active site of COX-2 protein. Collectively, compounds 7e, 7j, and 7k are all promising candidates for further research towards the development of novel anticancer agents.

Synthesis and in vitro antibacterial, antifungal, anti-proliferative activities of novel adamantane-containing thiazole compounds

A series of (Z)-N-(adamantan-1-yl)-3,4-diarylthiazol-2(3H)-imines (5a-r) was synthesized via condensation of 1-(adamantan-1-yl)-3-arylthioureas (3a-c) with various aryl bromomethyl ketones (4a-f). The structures of the synthesized compounds were characterized by 1H NMR, 13C NMR and by X-ray crystallography. The in vitro inhibitory activities of the synthesized compounds were assessed against a panel of Gram-positive and Gram-negative bacteria, and pathogenic fungi. Compounds 5c, 5g, 5l, 5m, and 5q displayed potent broad-spectrum antibacterial activity, while compounds 5a and 5o showed activity against the tested Gram-positive bacteria. Compounds 5b, 5l and 5q displayed potent antifungal activity against Candida albicans. In addition, the synthesized compounds were evaluated for anti-proliferative activity towards five human tumor cell lines. The optimal anti-proliferative activity was attained by compounds 5e and 5k which showed potent inhibitory activity against all the tested cell lines. Molecular docking analysis reveals that compounds 5e and 5k can occupy the positions of NAD cofactor and the histone deacetylase inhibitor EX527 at the active site of SIRT1 enzyme.

A newseries of thiazole-hydrazone hybrids for Akt-targeted therapy of non-small cell lung cancer.

In an attempt to identify potent antitumor agents for the fight against non-small cell lung cancer, new thiazolyl hydrazones (2a-n) were synthesized and examined for their in vitro cytotoxic effects on A549 human lung adenocarcinoma and L929 mouse embryonic fibroblast cells by means of theMTT assay. Furthermore, the effects of the most potent anticancer agents on apoptosis and Akt inhibition were investigated. 2-[2-((Isoquinolin-5-yl)methylene)hydrazinyl]-4-(4-methylsulfonylphenyl)thiazole (2k) (IC50 = 1.43 ± 0.12 µM) and 2-[2-((isoquinolin-5-yl)methylene)hydrazinyl]-4-(1,3-benzodioxol-5-yl)thiazole (2l) (IC50 = 1.75 ± 0.07 µM) displayed more pronounced anticancer activity than cisplatin (IC50 = 3.90 ± 0.10 µM) on A549 cell lines; 2-[2-((isoquinolin-5-yl)methylene)hydrazinyl]-4-(4-methoxyphenyl)thiazole (2j) (IC50 = 3.93 ± 0.06 µM) showed anticancer activity close to cisplatin. These compounds were found to induce apoptosis in A549 cells. Compound 2j (IC50 = 3.55 ± 0.64 µM) showed stronger Akt inhibitory activity than GSK690693 (IC50 = 4.93 ± 0.06 µM), while compounds 2k and 2l did not cause Akt inhibition at IC50 concentrations (1.43 and 1.75 µM, respectively). To comprehensively elucidate the binding pose of compound 2j and to provide a detailed understanding on the ligand' binding mechanism, induced-fit docking calculations were also conducted. Both in vitro and in silico studies suggest that compound 2j shows its cytotoxic and apoptotic effects on A549 cell linesvia Akt inhibition. However, it is understood that compounds 2k and 2l exert their strong anticancer effects on A549 cells through different pathways.

Synthesis of Novel Bis-imino and Bis-amino Curcuminoids for Evaluation of Their Anticancer and Antibacterial Activity.

A new set of curcumin analogues with a Schiff base moiety were synthesized from a bis-aldehyde derivative of hydroxybenzylidene cyclohexanone and various alicyclic and aromatic amines. The single crystals of compound 2 (bis-aldehyde), compound 3b (bis-cyclohexylimino derivative), and compound 3c (bis-1-imino piperidyl derivative) were developed. The said bis-imino and bis-amino curcuminoids were tested for anticancer activity against MCF-7 utilizing the conventional MTT assay. These Schiff bases had significantly higher anticancer efficacy than curcumin and methotrexate against MCF-7 cell lines. Compounds 3k, 3b, and 3l have the highest efficacy among all synthesized curcuminoids. The MTT results are in accordance with the binding affinities found by docking the said molecules with HER2 Tyrosine Kinase (HER2-TK). Compound 3b is identified as a promising HER2-TK inhibitor and also shows effective inhibition against Gram-positive bacteria Staphylococcus aureus.

In vitro and in silico assessment of bioactivity properties and pharmacokinetic studies of new 3,5-disubstituted-1,2,4-triazoles

The synthesis of new, more potent, with the least side effects and economical drugs is essential for the modern world. In search of such drug candidates, a biologically important moiety 1,2,4-triazole was introduced to bioactive piperidine to acquire a list of compounds, 8a-8n, with subtle structural variation. These compounds were synthesized from 4-chlorobenzene sulfonyl chloride (1) and piperidine-4-carboxylate (2) through a multistep synthesis of 5-{1-[(4-chlorophenyl)sulfonyl]-4-piperidinyl}-4-ethyl-4H-1,2,4-triazol-3-thiol (6) bearing bioactive moieties. The molecular structures were confirmed through FTIR, 1HNMR and 13CNMR. The in vitro enzyme inhibition potential of compounds was analyzed against acetyl cholinesterase (AChE), butyryl cholinesterase (BChE) and urease enzymes. Compound 8b bearing 2-chlorobenzyl group was the most active inhibitor of AChE and 8a bearing benzyl group of BChE with IC50 values (µM) of 32.43±0.53 and 68.14±0.34, respectively. Compounds 8k (IC50 1.78±0.12 µM), 8c (IC50 2.32±0.15 µM), 8a (IC50 3.09±0.42 µM), 8d (IC50 4.78±0.73 µM), 8f (IC50 6.58±0.91µM), 8h (IC50 11.25±1.12 µM), 8i (IC50 14.83±1.37 µM) and 8l (IC50 28.85±2.37 µM) were found potent inhibitors against the urease enzyme as compared with standard thiourea. Structure activity relationship (SAR) studies for urease inhibition displayed that compounds bearing n-propyl group (8k), 3,4-dichlorobenzyl group (8c), un-substituted benzyl group (8a) and 4-chlorobenzyl group (8d) were the most potent ones. Molecular docking studies showed that the compounds with aromatic substitution were better drug candidates in general. Antibacterial activity as determined by biofilm method showed some molecules active against gram positive bacteria. The hemolytic activity much inferred about the toxicity level of synthesized compounds. The chemo-informatics investigations including physicochemical properties and ADMET revealed that the most of the molecules had potential drug-likeness properties. Further work is required on the derivatization of the active compounds into more active ones as ‘lead’ compounds and is in progress.

Synthesis and molecular modeling studies of 1-benzyl-2-indolinones as selective AChEinhibitors.

Background: Possible bioisosteres can be developed by replacing the 1-indanone ring (one of three pharmacophore groups) of donepezil with an indoline ring. As H2S donors, thioamide, thiocarbamate and thiourea groups are also critically important. Materials & methods: The 1-benzyl-2-indolinones 6a-n were designed using molecular modeling and synthesized, and their acetylcholinesterase and butyrylcholinesterase inhibitory effects were then investigated. Results: The compounds 6h (inhibition constant [Ki] =0.22μM; selectivity index [SI] =26.22), 6i (Ki=0.24μM; SI=25.83), 6k (Ki=0.22μM; SI=28.31) and 6n (Ki=0.21μM; SI=27.14) were approximately twofold more effective against and >12-fold more selective for acetylcholinesterasecompared with donepezil (Ki=0.41μM; SI=2.12). Analysis of molecular dynamics simulations with compounds 6k and 6n indicated that the preferred binding might be at allosteric binding pocket 4 of the enzyme. Conclusion: Benzyl substitution at the 1-position of the indole ring significantly increased potency and selectivity.

Synthesis of new phenoxymethylcoumarin clubbed 4-arylthiazolylhydrazines as α-glucosidase inhibitors and their kinetics and molecular docking studies

The current studies mainly demonstrate the coumarin based azomethine-clubbed thiazoles synthesis and their in-vitro evaluation for the first time against α-glucosidase. Due to the catalytic role of α-glucosidase, it has become a precise target for the treatment of type diabetes mellitus (T2DM). The high rate of prevalence of diabetes and its associated health related problems led us to scrutinize the anti-diabetic capability of the synthesized thiazole derivatives (6a-6k). The anticipated structures of prepared compounds were confirmed through FT-IR and NMR spectroscopic methods. All the compounds showed several times potent activity than the standard drug, acarbose (IC50 = 873.34 ± 1.67 µM) against α-glucosidase with IC50 values in range of 0.87 ± 0.02–322.61 ± 1.14 µM. The compound 6k displayed the highest anti-diabetic activity (IC50 = 1.88 ± 0.03 µM). Kinetic study revealed that these are competitive inhibitors for α-glucosidase. The mode of binding of the synthesized molecules were further evaluated by molecular docking, which reflects the importance of azomethine group in protein–ligand interaction. The docking scores are complementary with the IC50 values of compounds while the interaction pattern of the compounds clearly demonstrates their structure–activity relationship. Current study reported medicinal importance of thiazole derivative as future drug candidates for the management of Type 2 Diabetes Mellitus (T2DM).