Compound 4m Research Articles

Microwave-assisted method to morpholinyl analogue and its effect on cadmium tolerance of soybean

A series of morpholiny analogues were efficiently obtained through nucleophilic aromatic substitution (SNAr) under microwave irradiation with simple operation. Furthermore, the molecular docking studies suggested that the compound 4m could bind receptor PYR1 much more strongly than abscisic acid. Significantly, the application of 4m could reduce the permeability of cell membranes to enhance the tolerance. Furthermore, the growth of root and above-ground parts and the fresh weight was improved when treatment with 4m under cadmium stress at 200–500 mg/L. Thus, compound 4m was successfully designed and synthesized as the most potent candidate.

Synthesis of quinoxalines and assessment of their inhibitory effects against human non-small-cell lung cancer cells.

Twenty-six quinoxalin derivatives were synthesized to assess their biological activities against human non-small-cell lung cancer cells (A549 cells). Compound 4b (IC50 = 11.98 ± 2.59 μM) and compound 4m (IC50 = 9.32 ± 1.56 μM) possess anticancer activity comparable to 5-fluorouracil (clinical anticancer drug) (IC50 = 4.89 ± 0.20 μM). Western blot tests further confirmed that compound 4m effectively induced apoptosis of A549 cells through mitochondrial- and caspase-3-dependent pathways. The introduction of bromo groups instead of nitro groups into the quinoxaline skeleton has been shown to provide better inhibition against lung cancer cells in this article. This modification in the molecular structure could enhance the biological activity and effectiveness of quinoxaline derivatives in the design and synthesis of anticancer drugs, making bromo-substituted quinoxalines a promising avenue for further research and development in anticancer therapeutics.

Tetrahydroisoquinoline-Triazole Derivatives: Novel Nicotinamide N-Methyltransferase Inhibitors

Through the Lilly Open Innovation Drug Discovery program (OIDD), we discovered five cationic bis(aryltriazol-4-yl)methyl)-6,7-dimethoxytetrahydroisoquinolinium derivatives that effectively inhibit human nicotinamide N-methyltransferase. Compounds 4a, 4c, and 4f demonstrated activity against hNNMT in enzymatic-based testing, with IC50 values of 3.177 μM, 7.9 μM, and 4.477 μM, respectively. In cell-based testing, 4c and 4f inhibited the enzyme in HEK293 cells with an IC50 value of 2.81 μM and 1.97 μM. Compound 4m inhibited hNNMT in the enzymatic-based assay by 98% at a concentration of 10 μM, with IC50 of 1.011 μM in the cell-based assay. Through structure-activity relationship analysis, we found that the active compounds had electron-withdrawing substituents at the 4-position of the phenyl-triazole, while compounds containing bulky and electron-donating groups at the same position did not display any activity. The results of docking studies using AutoDock 4.2 showed that all active compounds had similar binding patterns at the NNMT active site. They occupied the nicotinamide binding site and about two-thirds of the S-adenosyl-L-methionine site. However, the SAR and docking results of 4g contradicted the compound’s inactivity. Nevertheless, the molecular docking studies provided insight into how the ligands interact with the protein and explained the activity of our compounds.

Enantioselective Synthesis and Biological Evaluation of Pyrrolidines Bearing Quaternary Stereogenic Centers.

Molecular complexity plays an increasingly important role in the modern pharmaceutical industry. Setting up multiple stereogenic centers in privileged substructures may give rise to improved or even unprecedented bioactivities; however, this area remains largely unexplored due to the tremendous synthetic challenges. Herein, we report a series of multisubstituted pyrrolidines with four continuous stereogenic centers, including up to two aza-QSCs (quaternary stereogenic centers). Systematic evaluations, including phenotypic screening, molecular docking, molecular dynamics, bioinformatics, and bioactivity analysis, have been performed to screen entities with pharmacological properties of interest. Among them, compound 4m with two QSCs was identified to be a potent antiproliferation agent through disturbing mitosis exit, and the presence of QSCs was found to be crucial for anticancer efficacy. This work illustrates that the introduction of QSCs in privileged scaffolds not only helps to expand the unpatented chemical space but also provides new opportunities for the discovery of novel therapeutic agents.

Identification of Potent Inhibitors Targeting EGFR and HER3 for Effective Treatment of Chemoresistance in Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. Despite the existence of various therapeutic options, NSCLC is still a major health concern due to its aggressive nature and high mutation rate. Consequently, HER3 has been selected as a target protein along with EGFR because of its limited tyrosine kinase activity and ability to activate PI3/AKT pathway responsible for therapy failure. We herein used a BioSolveIT suite to identify potent inhibitors of EGFR and HER3. The schematic process involves screening of databases for constructing compound library comprising of 903 synthetic compounds (602 for EGFR and 301 for HER3) followed by pharmacophore modeling. The best docked poses of compounds with the druggable binding site of respective proteins were selected according to pharmacophore designed by SeeSAR version 12.1.0. Subsequently, preclinical analysis was performed via an online server SwissADME and potent inhibitors were selected. Compound 4k and 4m were the most potent inhibitors of EGFR while 7x effectively inhibited the binding site of HER3. The binding energies of 4k, 4m, and 7x were -7.7, -6.3 and -5.7 kcal/mol, respectively. Collectively, 4k, 4m and 7x showed favorable interactions with the most druggable binding sites of their respective proteins. Finally, in silico pre-clinical testing by SwissADME validated the non-toxic nature of compounds 4k, 4m and 7x providing a promising treatment option for chemoresistant NSCLC.

Design, Synthesis, and Anticancer Activity of Novel 3,6-Diunsaturated 2,5-Diketopiperazines.

Based on the marine natural products piperafizine B, XR334, and our previously reported compound 4m, fourteen novel 3,6-diunsaturated 2,5-diketopiperazine (2,5-DKP) derivatives (1, 2, 4-6, 8-16), together with two known ones (3 and 7), were designed and synthesized as anticancer agents against the A549 and Hela cell lines. The MTT assay results showed that the derivatives 6, 8-12, and 14 had moderate to good anticancer capacities, with IC50 values ranging from 0.7 to 8.9 μM. Among them, compound 11, with naphthalen-1-ylmethylene and 2-methoxybenzylidene functions at the 3 and 6 positions of 2,5-DKP ring, respectively, displayed good inhibitory activities toward both A549 (IC50 = 1.2 μM) and Hela (IC50 = 0.7 μM) cancer cells. It could also induce apoptosis and obviously block cell cycle progression in the G2/M phases in both cells at 1.0 μM. The electron-withdrawing functions might not be favorable for the derivatives with high anticancer activities. Additionally, compared to piperafizine B and XR334, these semi-N-alkylated derivatives have high liposolubilities (>1.0 mg mL-1). Compound 11 can be further developed, aiming at the discovery of a novel anticancer candidate.

Therapeutic potential of 1,3,4-oxadiazoles as potential lead compounds for the treatment of Alzheimer's disease.

Monoamine oxidase and cholinesterase enzymes are important targets for the treatment of several neurological diseases especially depression, Parkinson disease and Alzheimer's. Here, we report the synthesis and testing of new 1,3,4-oxadiazole derivatives as novel inhibitors of monoamine oxidase enzymes (MAO-A and MAO-B) and cholinesterase enzymes (acetyl and butyryl cholinesterase (AChE, BChE). Compounds 4c, 4d, 4e, 4g, 4j, 4k, 4m, 4n displayed promising inhibitory effects on MAO-A (IC50: 0.11-3.46 μM), MAO-B (IC50: 0.80-3.08 μM) and AChE (IC50: 0.83-2.67 μM). Interestingly, compounds 4d, 4e and 4g are multitargeting MAO-A/B and AChE inhibitors. Also, Compound 4m displayed promising MAO-A inhibition with IC50 of 0.11 μM and high selectivity (∼25-fold) over MAO-B and AChE enzymes. These newly synthesized analogues represent promising hits for the development of promising lead compounds for neurological disease treatment.

Investigation of Novel Quinoline-Thiazole Derivatives as Antimicrobial Agents: In Vitro and In Silico Approaches.

Infectious diseases are a major concern around the world. Today, it is an urgent need for new chemotherapeutics for infectious diseases. Because of that, our group designed, synthesized, and analyzed 14 new quinoline derivatives endowed with the pharmacophore moiety of fluoroquinolones primarily for their antimicrobial effects. Their cytotoxicity effects were tested against six bacterial and four fungal strains and NIH/3T3 cell line. Additionally, their action mechanisms were evaluated against DNA gyrase and lanosterol 14α-demethylase (LMD). Furthermore, to eliminate the potential side effects, the active compounds were evaluated against the aromatase enzyme. The experimental enzymatic results were evaluated for active compounds' binding modes using molecular docking and molecular dynamics simulation studies. The results were utilized to clarify the structure-activity relationship (SAR). Finally, compound 4m was the most potent compound for its antifungal activity with low cytotoxicity against healthy cells and fewer possible side effects, while compounds 4j and 4l can be used alone for special patients who are suffering from fungal infections in addition to the primer disease.

Natural products as sources of acetylcholinesterase inhibitors: Synthesis, biological activities, and molecular docking studies of osthole-based ester derivatives.

Osthole is a natural coumarin compound which isolated from Cnidium monnieri (L.) Cusson, has extensive pharmacological activities and could be used as a leading compound for drug research and development. In a continuous effort to develop new acetylcholinesterase inhibitors from natural products, eighteen osthole esters were designed, synthesized, and confirmed by 1H NMR, 13C NMR and HRMS. The anti-AChE activity of These derivatives was measured at a concentration of 1.0 mol/mL in vitro by Ellman's method, and the result showed that 4m and 4o had moderate inhibitory activities with 68.8% and 62.6%, respectively. Molecular docking study results further revealed AChE interacted optimally with docking poses 4m and 4o. Network pharmacology also predicted that compound 4m could be involved in Ras signaling pathway, which made it a potential therapeutic target of AD.

Design, synthesis, cytotoxicity, and molecular docking studies of 1-(4-methoxyphenyl)-N-substituted phenyl-1H-1,2,3-triazole-4-carboxamide derivatives

A new series of 1-(4-methoxyphenyl)-N-substituted phenyl-1H-1,2,3-triazole-4-carboxamide derivates (4A–4N) have been synthesized in excellent yields and structures were characterized by spectral techniques like 1H-NMR, 13C-NMR, LC-MS, and FT-IR. The newly synthesized derivatives were evaluated for anticancer activity against breast cancer cell lines MCF-7 and MDA-MB-231. Among them, compound 4H (IC50 = 13.11 and 23.61 μM) and compound 4M (IC50 = 11.55–31.87 μM) shows good cytotoxicity activity toward both cell line, while compounds 4B (IC50 = 9.48 μM), 4I (IC50 = 7.11 μM), and 4J (IC50 = 8.27 μM) showed promising cytotoxicity against MCF-7 cell line as compared with standard (Doxorubicin). Also explored docking study with binding mode of interactions and active site in EGFR tyrosinse (PDB ID: 2J5F) proteins and molecular docking study shows very good interaction with the tyrosine kinase active site. In addition to this targeted compounds were studied the pharmacokinetics and the compounds were follow Lipinski’s rule of five as well as compounds have acceptable good drug-likeness score properties.

Design, synthesis, in vitro α-glucosidase inhibition, docking, and molecular dynamics of new phthalimide-benzenesulfonamide hybrids for targeting type 2 diabetes

In the present work, a new series of 14 novel phthalimide-benzenesulfonamide derivatives 4a–n were synthesized, and their inhibitory activity against yeast α-glucosidase was screened. The obtained results indicated that most of the newly synthesized compounds showed prominent inhibitory activity against α-glucosidase. Among them, 4-phenylpiperazin derivative 4m exhibited the strongest inhibition with the IC50 value of 52.2 ± 0.1 µM. Enzyme kinetic study of compound 4m proved that its inhibition mode was competitive and Ki value of this compound was calculated to be 52.7 µM. In silico induced fit docking and molecular dynamics studies were performed to further investigate the interaction, orientation, and conformation of the target compounds over the active site of α-glucosidase. Obtained date of these studies demonstrated that our new compounds interacted as well with the α-glucosidase active site with the acceptable binding energies. Furthermore, in silico druglikeness/ADME/Toxicity studies of compound 4m were performed and predicted that this compound is druglikeness and has good ADME and toxicity profiles.

Design, synthesis, molecular modeling and DNA-binding studies of new barbituric acid derivatives

Cancer disease is developing all over the world mainly in developing countries. We should learn more about DNA–ligand interactions to design new drugs that target biological activities like transcription, replication and translation of particular genes. To understand the mechanism of action and design-specific DNA binders, the evaluation of DNA–ligand interactions is critical. Novel barbituric acid derivatives based on (benzyloxy)benzaldehydes were synthesized and evaluated as DNA-binding agents. Among products, molecular docking studies revealed that 4j and 4m have the best interactions with the ctDNA via the minor groove binding. These results were approved by the quantum mechanics calculations. The interaction profiles of the selected compound (4j and 4m) with DNA were evaluated by UV–Visible titration. UV–Visible titration data confirm this interaction. According to the molecular modeling results, the Structure–Activity relationships for all synthesized barbituric acid derivatives were proposed. It was observed that N,N-dimethyl barbituric acid/4-hydroxybenzaldehyde derivatives have better DNA interactions than barbituric acid/vanillin and barbituric acid/3-hydroxybenzaldehyde derivatives.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13738-022-02576-x.

Synthesis and structure-activity relationship study of a potent MHO7 analogue as potential anti-triple negative breast cancer agent

Triple-negative breast cancer (TNBC) is the most aggressive, high recurrence and metastatic breast cancer subtype. There are few safe and effective therapeutic drugs for treatment of TNBC. The marine natural product MHO7 has been determined to be a potential antitumor agent. However, its moderate activity and complex structure hampered its clinical application. In this study, a series of novel derivatives with modification on C24 of MHO7 were first synthesized. Some of the analogues were significantly more potent than MHO7 against all selected breast cancer cell lines. Among them, compound 4m had the best activity, and its IC50 value against TNBC was up to 0.51 μM. A whole-genome transcriptomic analysis shown that the mechanism of compound 4m against TNBC cells was similar with that of parent compound MHO7. Subsequent cellular mechanism studies showed that compound 4m could induce apoptosis of MDA-MB-231 cells through mitochondria pathway and cause G1 phase arrest. Moreover, 4m could disrupt the expressions of MAPK/Akt pathway-associated proteins (p-p38 and p-Akt) and remarkably increase the ratio of Bax to Bcl-2 and activate cleaved caspase 3/9/PARP. Importantly, 4m could influence the expression of Smad 7, and p-Smad 3 to inhibit TNBC cells metastasis. Stability assays in rat plasma and liver microsomes indicated that 4m still have room for further optimization. And the results of the online molinspiration software predicted that 4m has desirable physicochemical properties but some properties still have violation from the Lipinski rule of five. Overall, the modification on C24 of MHO7 was a promising way for developing novel anti-TNBC agents with considerable potential for optimization.

Design, synthesis and in vitro biological activities of coumarin linked 1,3,4-oxadiazole hybrids as potential multi-target directed anti-Alzheimer agents

IntroductionAlzheimer’s disease (AD) is one of the most common and prevalent forms of neurodegenerative diseases. Coumarin is a versatile scaffold that exhibits a wide range of biological properties including cholinesterase inhibitory activity and therefore is an important heterocyclic moiety to develop anti-AD drugs. ObjectivesThis study aimed to design and synthesize coumarin linked 1,3,4-oxadiazole hybrid derivatives as multi-target directed ligands (MTDLs) and to investigate their in vitro anticholinesterase, antioxidant and anti-inflammatory activities. MethodsTwo series (4a-n and 7a-m) of low molecular weight ligands (27 compounds) containing coumarin linked 1,3,4-oxadiazole hybrids were synthesized and their chemical structures were characterized using analytical data. In vitro acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) inhibitory activity, antioxidant activity and cyclooxygenase (COX) inhibitory activity were investigated following standard spectrophotometric methods. Molecular docking studies to predict the binding mode with AChE and BuChE in addition to the pharmacokinetic profile of the synthesized compounds were studied with the help of online cheminformatics software. ResultsAmongst the tested compounds for anticholinesterase activity, 4e and 4g hybrid derivatives were found to be the most potent AChE inhibitors (IC50 values = 29.56 and 28.68 μM), respectively. Compound 4m exhibited the maximum inhibitory activity against BuChE (IC50 value = 23.97 μM). Compounds 4g and 4e also showed higher selectivity index (SI) of 1.652 and 1.552 as compared to standard galantamine (SI = 1.132). Molecular docking studies revealed that 4g and 4e, two most potent AChE inhibitors identified through in vitro assay, binds well to AChE (binding energy scores of −9.7 and −10.1 Kcal/Mol). Synthesized hybrid molecules also exhibited good to excellent in vitro antioxidant and anti-inflammatory activities. ConclusionBased on the results of in vitro and in-silico studies, it could be concluded that coumarin-oxadiazole hybrids acts as MTDLs and are promising source of anti-AD drugs. Further detailed investigations and modification of these compounds can lead to the development of highly potent therapeutics for the treatment of AD.

Synthesis and Antitumor Activity of Erlotinib Derivatives Linked With 1,2,3-Triazole.

Cervical cancer is one of the most important cause of cancer-related death and presents a major public health problem in many countries. To search for more novel antitumor agents against cervical cancer, 14 erlotinib-linked 1,2,3-triazole compounds were designed, synthesized, and evaluated for their anti-tumor activity. The compounds were confirmed by 1H NMR, 13C NMR, and high-resolution mass spectra (HR MS). Antitumor activity assay results indicated that six of those compounds have remarkable inhibitory activity against human cervical cancer HeLa cells in vitro, among which compound 4m was the most potent with IC50 of 3.79 μM, and compounds 4k, 4i, 4l, 4d, and 4n also demonstrated remarkable antitumor activity with IC50 of 3.79, 4.16, 4.36, 7.02, and 8.21 μM. We found three of the most potent compounds 4d, 4k, and 4l induced potent apoptosis and cell cycle arrest in HeLa cells, and compounds 4d and 4l significantly restrained the cell colony formation and showed moderate epidermal growth factor receptor (EGFR) inhibitory activity with IC50 of 13.01 and 1.76 μM. Therefore, these experiments indicate that these erlotinib-linked 1,2,3-triazole compounds are potential to act as effective anticancer agents against cervical cancer.

Design, synthesis, and in vitro antitumor activity of 6-aryloxyl substituted quinazoline derivatives.

Quinazoline derivatives are a class of important antitumor drugs known as small molecule inhibitors that include epidermal growth factor receptor (EGFR) inhibitors. Based on the structure of poziotinib, a series of 6-aryloxyl substituted quinazoline derivatives were designed and synthesized. The in vitro antitumor activities of the compounds were evaluated by the 3-(4,5-dimethyl-thiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) method using the human gastric cancer N87 (HER2), nonsmall-cell lung cancer H1975 (EGFRT790M/L858R), and A549 (EGFRWT) cell lines. The most promising compound 4m exhibited potent antitumoral activities with IC50 values of 6.3 nM and 7.5 nM for N87 and H1975 cell lines, respectively. Meanwhile, it was less potent against A549 cancer cells with an IC50 value of 29.9 μM. The molecular docking results suggested that compound 4m has different binding modes to the wild-type and mutated EGFR.

Synthesis, Molecular Docking and Biological Evaluation of Napthyl N-Acyl Hydrazone Derivatives

A series of 2-(benzamido)-N′-((naphthalen-1-yl)methylene)-3-(substituted phenyl)acrylo hydrazides (4a-m, 5a-b) were synthesized by condensation of 2-(benzamido)-3-(substituted phenyl)acrylohydrazides with 1-naphthaldehyde in presence of few drops of acetic acid in ethanol. Structural elucidation of final compounds was confirmed by spectral data. Title compounds were evaluated for antioxidant and antibacterial activities and subjected to in silico studies and molecular docking studies with cyclooxygenase-II (COX-II, PDB I’d: 3LN1) and active compounds from docking studies were selected for in vivo evaluation of their antiinflammatory activity. Among the series, compound 4i showed good antioxidant activity; 5b showed good antibacterial activity. All the six derivatives with good docking scores were selected for in vivo evaluation of their antiinflammatory activity. Among the selected active compounds from docking studies, compound 4m showed good antiinflammatory activity which is comparable with that of standard drug diclofenac. In silico studies indicated that all the compounds followed Lipinski’s rule and exhibited good oral absorption and bioavailability.

Amino acid ionic liquid-catalyzed synthesis, anti-Leishmania activity, molecular docking, molecular dynamic simulation, and ADME study of 3,4-dihydropyrimidin-2(1H)-(thio)ones

The synthesis of 3,4-dihydropyrimidin-2(1H)-(thio)one (DHPM) derivatives involving aromatic aldehyde, β-ketoesters and urea/thiourea using prolinium hydrogen sulfate (ProHSO4) as a catalyst has been studied. A variety of DHPM derivatives were obtained in high yield under solvent-free conditions in a short reaction time. The in-vitro screening of antileishmanial activity of both the oxo and the thioxo compounds showed significant activity against extracellular promastigotes. The aldehyde substituted at C-4 position with methyl (4g) in the oxo series and chloro (4m), methyl (4n) in the thioxo series imparted good bioactivity, with >80% reduction in viability at 50 µg/mL, with IC50 values 29.3, 29.3, and 28.3 µg/mL, respectively. Molecular docking study of the compound 4m displayed −6.4 kcal/mol binding energy. According to 50 ns molecular dynamics simulation study Leishmania major pteridine reductase 1 (PTR1) interacts well with the amino acid residues Phe-109, Leu-222, and Val-226. The in silico ADME study showed good drug-likeness properties.

Discovery and preliminary mechanism of 1-carbamoyl β-carbolines as new antifungal candidates.

Natural β-carboline alkaloids are ideal models for the discovery of pharmaceutically important entities. Various 1-substituted β-carbolines were synthesized from commercially inexpensive tryptophan and demonstrated significant invitro antifungal activity against G.graminis. Significantly, compound 4m (EC50=0.45μM) with carboxamide at 1-position displayed the best efficacy and nearly 20 folds enhancement in antifungal potential compared to Silthiopham (EC50=8.95μM). Moreover, compounds 6, 7, and 4i exhibited excellent invitro antifungal activities and invivo protective and curative activities against B.cinerea and F.graminearum. Preliminary mechanism studies revealed that compound 4m caused reactive oxygen species accumulation, cell membrane destruction, and deregulation of histone acetylation. These findings indicated that 1-carbamoyl β-carboline can be selected as a promising model for the discovery of novel and broad-spectrum fungicide candidates.

Computer-aided Validation of Fluorobenzimidazole as Soluble Epoxide Hydrolase Inhibitor: An In-Silico Study

Soluble epoxide hydrolase (sEH) is an enzyme and is encoded by the gene EPHX2 in human beings. Indeed, by inhibiting the biotransformation of these epoxide(s) via arresting the action of the mammalian sEH one can develop a promising antihypertensive drug(s). The present work was emphasized the possible binding mode of fifteen fluorobenzimidazole (4a-4o) derivatives as soluble epoxide hydrolase (sEH) inhibitors. The X-ray crystal structure of human sEH in complex with the inhibitor 6NJ [(3-(2-phenylethyl)-1H-indazole] has been utilized to select the specific active site of protein data bank (PDB) ID: 5AKY with resolution: 2.18 Å for the docking study.The energy conformer of trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (tAUCB) was docked using the prepared grid towards validation of the generated grid and docking protocol. The best results obtained by the ligands 4f, 4g and 4m with a dock score -9.94, -9.75, and -11.56, respectively. Among all the ligands, 4m exhibited considerable “drug-like” characteristics with the highest G score and possess acceptable in-silico pharmacokinetic by obeying Lipinski rule of five. In conclusion, compound 4m might be used as a lead molecule in the antihypertensive drug discovery.