Design, synthesis, cytotoxicity, and molecular docking studies of 1-(4-methoxyphenyl)-N-substituted phenyl-1H-1,2,3-triazole-4-carboxamide derivatives (original) (raw)
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Synthetic Communications
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 1 H-NMR, 13 C-NMR, LC-MS & 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 (IC 50 = 13.11 µM and 23.61 µM) and compound 4M (IC 50 = 11.55µM to 31.87µM) shows good cytotoxicity activity toward both cell line, while compounds 4B (IC 50 = 9.48 µM), 4I (IC 50 = 7.11 µM), and 4J (IC 50 = 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 tyrosinse kinase active site. In addition of this targeted compounds were studied the pharmacokinetic and the compounds were follow Lipinski's rule of ve as well as compounds have acceptable good drug-likeness score properties.
Journal of Molecular Graphics & Modelling, 2018
This paper deals with in silico evaluation of newly proposed heterocyclic derivatives in search of potential anticancer activity. Best possible drug candidates have been proposed using a rational approach employing a pipeline of computational techniques namely MetaPrint2D prediction, molinspiration, cheminformatics, Osiris Data warrior, AutoDock and iGEMDOCK. Lazar toxicity prediction, AdmetSAR predictions, and targeted docking studies were also performed. 27 heterocyclic derivatives were selected for bioactivity prediction and drug likeness score on the basis of Lipinski's rule, Viber rule, Ghose filter, leadlikeness and Pan Assay Interference Compounds (PAINS) rule. Bufuralol, Sunitinib, and Doxorubicin were selected as reference standard drug for the comparison of molecular descriptors and docking. Bufuralol is a known non-selective adreno-receptor blocking agent. Studies showed that beta blockers are also used against different types of cancers. Sunitinib is well known Food and Drug administration (FDA) approved pyrrole containing tyrosine kinase inhibitor and our proposed molecules possess similarities with both drug and doxorubicin is another moiety having anticancer activity. All heterocyclic derivatives were found to obey the drug filters except standard drug Doxorubicin. Bioactivity score of the compounds was predicted for drug targets including enzymes, nuclear receptors, kinase inhibitors, G protein-coupled receptor (GPCR) ligands and ion channel modulators. Absorption, distribution, metabolism and toxicity (ADMET) prediction of all proposed compound showed good Blood-brain barrier (BBB) penetration, Human intestinal absorption (HIA), Caco-2 cell permeability except compound-11 and was found to have no AdmetSAR toxicity as well as carcinogenic effect. Compounds 1-9 were slightly mutagenic while compound 2, 11, 20 and 21 showed carcinogenic effect according to Lazar toxicity prediction. Rests of the compounds were predicted to have no side effect. Molecular docking was performed with vascular endothelial growth factor receptor-2(VEGFR2) and glutathione Stransferase-1(GSTP1) because both are common cancer causing proteins. Sunitinib and Doxorubicin possess great affinity to inhibit these cancers causing protein. Self-organizing map (SOM) was used to depict data in a simple 2D presentation. Our studies justify that good oral bioavailability and therapeutic efficacy of 10, 12-19 and 22-27 compounds can be considered as potential anticancer agents.
Molecular Docking Studies of Enzyme Inhibitors and Cytotoxic Chemical Entities
Molecular Docking, 2018
Docking is a powerful approach to perform virtual screening on large library of compounds, rank the conformations using a scoring function, and propose structural hypotheses of how the ligands inhibit the target, which is invaluable in lead optimization. Using experimentally proven active compounds, detailed docking studies were performed to determine the mechanism of molecular interaction and its binding mode in the active site of the modeled yeast α-glucosidase and human intestinal maltase-glucoamylase. All active ligands were found to have greater binding affinity with the yeast α-glucosidase as compared to that of human homologs, intestinal, and pancreatic maltase, by an average value of~À1.3 and~À0.8 kcal/ mol, respectively. Thirty quinoline derivatives have been synthesized and evaluated against β-glucuronidase inhibitory potential. Twenty-four analogs, which showed outstanding βglucuronidase activity, have IC 50 values ranging between 2.11 AE 0.05 and 46.14 AE 0.95 μM than standard D-saccharic acid 1,4-lactone (IC 50 = 48.4 AE 1.25 μM). Structure activity relationship and the interaction of the active compounds and enzyme active site with the help of docking studies were established. In addition, Small series of morpholine hydrazones synthesized to form morpholine hydrazones scaffold. The in vitro anti-cancer potential of all these compounds were checked against human cancer cell lines such as HepG2 (Human hepatocellular liver carcinoma) and MCF-7 (Human breast adenocarcinoma). Molecular docking studies were also performed to understand the binding interaction.
Substituted thiazolidinone linked to benzothiazoles and benzoxazoles 3a,b or substituted 5-benzylidene-4thiazolidinones 4a-h were synthesized. The antitumor activity of the prepared compounds was evaluated against human breast MCF7 and liver HEPG2 cancer cell lines using Sulphorhodamine-B (SRB) assay method, doxorubicin was used as a reference standard. Most of the tested compounds showed potent antitumor activity especially the pmethoxy-5-benzylidine-4-thiazolidinone derivative of benzoxazole 4c and benzothiazole 4d, their IC 50 against liver HEPG2 cancer cell line are 0.027 nM and 0.026 nM respectively. The IC 50 of p-chloro-5-benzylidine-4thiazolidinone linked to benzoxazole 4e against breast MCF7 cancer cell line, is 19 nM but, p-nitro-5-benzylidine-4-thiazolidinone derivative of benzothiazole 4h showed a broad spectrum antitumor activity against MCF7 and HEPG2 cell lines, its IC 50 is 36 and 48 nM respectively. The most active compounds were docked against VEGFR-2 using Moe program and 1Y6A (pdb file) to investigate if these compounds had a similar binding mode to VEGFR-2 inhibitors.
Systematic Reviews in Pharmacy, 2021
Objectives: New derivatives of 2-(1-(2-flouro-[1,1-biphenyl]-4-yl)ethyl)-6-(substituted phenyl) imidazole[2,1-b][1,3,4]thiadiazole, compounds(2-5), were designed and synthesized from the starting parent molecule, flurbiprofen. Materials and Methods: Compound (1) was synthesized by refluxing flurbiprofen, as a starting material , with phosphorus oxychloride (POCl3), and thiosemicarbazide, resulting in flurbiprofen-1,3,4 thiadiazole-2 amine derivative. The target compounds(2-5) were obtained by refluxing compound(1) with different substituted phenacyl bromides, Results: The new compounds were characterized by FTIR, 1 HNMRs and CHNS analysis. A molecular docking study of the synthesized compounds (2-5) against HIV protease indicated such compounds occupied the critical site of HIV protease pocket, and demonstrated excellent positioning of the compounds in the pocket. The best binding energy values were (-7.49,-7.22 ,-7.51 and-7.12 kcal/mol) for the compounds (2 5 , respectively. The anticipated physiochemical parameters(calculated logarithmic of partition cofficent(Clog p),molecular volume (MV), number of violations (nviol), topological surface area (TPSA), and percent of absorption(%Abs.) were computed using software Molinspiration. In vitro outcomes, the target compounds were assessed by cell line study for their anticancer effects. All the tested compounds showed the most plausible anticancer activity, when compared to a positive control (atazanavir), using MTT cytotoxic assay, against human prostatic tumor (PC 3), glioma cell line (LN68), and normal WRL-68 cell line. Conclusion: The results revealed that compounds 2,3,4 and 5 exhibited the highest inhibitory activity against PC3 cell line at IC50 concentrations of 178.2, 75.09, 129.3and 110.5μg/mL, respectively, and they had moderate effects against LN299 cell line at IC50 concentrations 203,172.5, 169,and 157.7 μg/mL, respectively, compared to atazanavir, as a positive control against PC 3, at IC50, 157.3 μg/mL, and in LN299, at IC50 195.7 μg/mL. Also compound (5) attributed to cell-cycle arrest, and induction of apoptosis. The target compounds could be considered as promising as potential anticancer drugs.
Design and synthesis of 2- phenyl benzimidazole derivatives as VEGFR- 2 inhibitors with anti- breast cancer activity , 2018
Three new series of 2- phenyl benzimidazole- based derivatives were designed, synthesized, and evaluated for their in vitro cytotoxic activity against breast cancer (MCF- 7) cell lines. Three compounds 8, 9, and 15 showed high cytotoxic activities, with IC50 values of 3.37, 6.30, and 5.84 μM, respectively, while they showed comparable cytotoxicity to the standard drug doxorubicin against human normal cells, including nontumorigenic breast epithelial cell line (MCF- 10F), skin fibroblast cell line (BJ), and lung fibroblast cell line (MRC- 5). Six of the synthesized compounds were screened against vascular endothelial growth factor receptor 2 (VEGFR- 2) where compounds 8, 9, 12, and 15 exhibited an outstanding potency in comparison with sorafenib, with IC50 values of 6.7–8.9 nM. Molecular docking study assessed the good binding patterns of the most potent compounds with the reported conserved amino acids of VEGFR- 2 active site.
Anti-Cancer Agents in Medicinal Chemistry
Bentham sciences, 2022
Cancer has emerged as one of the leading causes of death globally, partly due to the steady rise in anticancer drug resistance. Pyrimidine and pyrimidine-fused heterocycles are some of the privileged scaffolds in medicine, as they possess diverse biological properties. Pyrimidines containing azole nucleus possess inestimable anticancer potency and can potentially regulate cellular pathways for selective anticancer activity. The present review outlines the molecular structure of pyrimidine-fused azoles with significant anticancer activity. The structure activity relationship and molecular docking studies have also been discussed. The current review is the first complete compilation of significant literature on the proposed topic from 2016 to 2020. The information contained in this review offers a useful insight to chemists in the design of new and potent anticancer azole-pyrimidine analogues.
Bioorganic & Medicinal Chemistry, 2009
The synthesis, in vivo and in vitro antitumor evaluation, and QSAR studies of some novel pyrazole analogs against Ehrlich Ascites Carcinoma (EAC) cells were described. In vitro results revealed that compounds 10, 6 and 4 were the most potent analogs against EAC, respectively. Moreover, in vivo evaluation of compounds 6 and 10 proved their capability to normalize the blood picture in comparison to 5-FU, a well known anticancer drug. These novel pyrazole analogs were molecularly designed with the goal of having significant potent cytotoxic effect against EAC cells. To develop a QSAR model capable of identifying the key molecular descriptors associated with the biological activity of the novel pyrazole analogs and predicting the cytotoxic effect for other novel pyrazole analogs against EAC cells, different QSAR models, using different physicochemical and topological molecular descriptors, were developed. Different molecular descriptors were predicted solely from the chemical structures of 16 pyrazolo-diazine and triazine analogs following the prediction of the equilibrium molecular geometry of each analog at the DFT level using B88-LYP functional energy and double zeta valence polarized (DZVP) basis set. It was found that dipole moment, excitation energy, the energy value of LUMO, solvent accessible surface area, and heat of formation were the key molecular descriptors in descriping the cytotoxic effect of those compounds against EAC.
ChemistrySelect, 2020
Searching the organic compound as anti-inflammatory agent is a fruitful effort to treat inflammatory disorders such as asthma, arthritis, psoriasis, and especially cancer. These disorders can be cured by lipoxygenase (LOX) inhibitors, which have the ability to stop the development and progression of inflammation. The present research described the synthesis of fifteen new N-alkyl/ aralkyl/aryl derivatives (7 a-o) of 2-(4-ethyl-5-(1-phenylcarbamoyl)piperidine-4H-1,2,4-triazol-3-ylthio)acetamide by the continuous conversions of ethyl piperidine-4-carboxylate (a) into phenylcarbamoyl derivative (1) hydrazide (2), semicarbazide (3) and finally the N-ethylated 5-(1-phenylcarbamoyl)piperidine-1,2,4-triazole (4). The target molecules (7 a-o) were formed by the reaction of 4 with various electrophiles (6 a-o), in methanolic potassium hydroxide. These synthetic analogues were characterized by FTIR, 1 H, 13 C NMR spectroscopy, EIMS, and HREIMS spectrometry. The compounds 7 a-o were screened for their inhibitory potential against 15-lipoxygenase. Compounds 7 b, 7 e, 7 c and 7 g displayed the potent inhibitory potential (IC 50 17.52 � 0.67, 35.61 � 0.81, 36.24 � 0.83 & 36.52 � 0.58 μM, respectively), whereas, moderate inhibition was shown by 7 h, 7 a, 7 d with IC 50 values between 42.95 � 0.73 to 45.67 � 0.75 μM, respectively. Some compounds exhibited drug-like characteristics due to their lower cytotoxic and good ADME profiles and supported by molecular modeling studies where one of the NH groups was found engaged through hydrogen bonding with Ala672. The carbonyl group amide and Asn554 were connected by a hydrogen bond, whereas the second NH group was also linked through hydrogen bonds with Gln363.
Drug Design, Development and Therapy
The objective of our work was to prepare a potent and safe antimicrobial and anticancer agents, through synthesis of several peptides and examine their biological activities, namely as, cytotoxically potent and antimicrobial and antifungal agents. Introduction: Multidrug-resistant microbial strains have arisen against all antibiotics in clinical use. Infections caused by these bacteria threaten global public health and are associated with high mortality rates. Methods: The main backbone structure for the novel synthesized linear peptide is Nα-1, 3benzenedicarbonyl-bis-(Amino acids)-X, (3-11). A computational docking study against DNA gyrase was performed to formulate a mode of action of the small compounds as antimicrobial agents. Results: The peptide-bearing methionine-ester (4) exhibited potent antimicrobial activity compared to the other synthesized compounds, while, peptide (8), which had methioninehydrazide fragment was the most potent as antifungal agent against Aspergillus niger with 100% inhibition percent. Compounds (6 and 7) showed the highest potency against breast human tumor cell line "MCF-7" with 95.1% and 79.8% of cell inhibition, respectively. The nine compounds possessed weak to moderate antiproliferative effect over colon tumor cell line. The docking results suggest good fitting through different hydrogen bond interactions with the protein residues. In silico ADMET study also evaluated and suggested that these compounds had promising oral bioavailability features. Conclusion: The tested compounds need further modification to have significant antimicrobial and antitumor efficacy compared to the reference drugs.