Rationale Design, Synthesis, Cytotoxicity Evaluation, and Molecular Docking Studies of 1,3,4-oxadiazole Analogues

2018 ◽  
Vol 18 (1) ◽  
pp. 121-138 ◽  
Author(s):  
Mohamed Jawed Ahsan ◽  
Arun Choupra ◽  
Rakesh Kumar Sharma ◽  
Surender Singh Jadav ◽  
Pannala Padmaja ◽  
...  
Keyword(s):  
Biological Activities ◽  
Aromatic Aldehydes ◽  
Docking Studies ◽  
Cytotoxic Agents ◽  
Tubulin Polymerization ◽  
Sodium Bisulphite ◽  
Tubulin Inhibitor ◽  
Tubulin Inhibitors ◽  
Drug Concentrations

Background: 1,3,4-Oxadiazole heterocycles possess a broad spectrum of biological activities. They were reported as potent cytotoxic agents and tubulin inhibitors; hence it is of great interest to explore new oxadiazoles as cytotoxic agents targeting tubulin polymerization. Objective: Two new series of oxadiazoles (5a-h and 12a-h) were synthesized, structurally related to the heterocyclic linked aryl core of IMC-038525, NSC 776715, and NSC 776716, with further modification by incorporating methylene linker. Method: The 2,5-disubstituted-1,3,4-oxadiazoles (5a-h and 12a-h) were synthesized by refluxing an equimolar mixture of the intermediates [(4) and (8a-d)] and aromatic aldehydes in water-ethanol system using sodium bisulphite catalyst. The cytotoxicity evaluation was carried out according to the National Cancer Institute (NCI US) Protocol, while the tubulin polymerization assay kits from Cytoskeleton ™(bk011p) was used to perform an in vitro tubulin polymerization assay. Results: 2-(5-{[(4-Chlorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)phenol (5f) and 2-[(2,4-dichlorophenoxy) methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole (12c) showed maximum cytotoxicity with the mean percent growth inhibitions (GIs) of 71.56 and 72.68 respectively at 10 µM drug concentrations. Both the compounds (5f and 12c) showed superior cytotoxicity than clinically prevalent anticancer drugs, Imatinib and Gefitinib in one dose assay. The compound 12c showed promising results in five dose assay, with GI50 values varies between 1.61 and >100 µM. Furthermore, the compounds, 5f and 12c also inhibited the polymerization of tubulin with, an IC50 of 2.8 and 2.2 µM, respectively. Conclusion: The oxadiazoles reported herein are tubulin inhibitors and cytotoxic agents. These findings will be helpful in future drug design of more potent tubulin inhibitor cytotoxic agents.

scholarly journals Exploring Diverse-Ring Analogues on Combretastatin A4 (CA-4) Olefin as Microtubule-Targeting Agents

2020 ◽  
Vol 21 (5) ◽  
pp. 1817 ◽  
Author(s):  
Ming-Yu Song ◽  
Qiu-Rui He ◽  
Yi-Lin Wang ◽  
Hao-Ran Wang ◽  
Tian-Cheng Jiang ◽  
...  
Keyword(s):  
Hepg2 Cells ◽  
Annexin V ◽  
Docking Studies ◽  
Cytotoxic Agents ◽  
Tubulin Polymerization ◽  
Microtubule Network ◽  
Microtubule Targeting Agents ◽  
Ic50 Values ◽  
Tubulin Polymerization Inhibitor

Combretastatin-4 (CA-4) as a tubulin polymerization inhibitor draws extensive attentions. However, due to its weak stability of cis-olefin and poor metabolic stability, structure modifications on cis-configuration are being performed. In this work, we constructed a series of novel CA-4 analogues with linkers on olefin containing diphenylethanone, cis-locked dihydrofuran, α-substituted diphenylethanone, cyclobutane and cyclohexane on its cis-olefin. Cytotoxic activity of all analogues was measured by an SRB assay. Among them, compound 6b, a by-product in the preparation of diphenylethanone analogues, was found to be the most potent cytotoxic agents against HepG2 cells with IC50 values of less than 0.5 μM. The two isomers of 6b induced cellular apoptosis tested by Annexin V-FITC and propidium iodide (PI) double staining, arrested cells in the G2/M phase by PI staining analysis, and disrupted microtubule network by immunohistochemistry study in HepG2 cells. Moreover, 6b-(E) displayed a dose-dependent inhibition effect for tubulin assembly in in vitro tubulin polymerization assay. In addition, molecular docking studies showed that two isomers of 6b could bind efficiently at colchicine binding site of tubulin similar to CA-4.

Novel Iodinated Hydrazide-hydrazones and their Analogues as Acetyl- and Butyrylcholinesterase Inhibitors

2020 ◽  
Vol 20 (23) ◽  
pp. 2106-2117
Author(s):  
Martin Krátký ◽  
Šárka Štěpánková ◽  
Michaela Brablíková ◽  
Katarína Svrčková ◽  
Markéta Švarcová ◽  
...  
Keyword(s):  
Biological Activities ◽  
Structural Parameters ◽  
Covalent Binding ◽  
Docking Studies ◽  
Potent Inhibition ◽  
Brain Barrier Permeability ◽  
Electric Eel ◽  
Ic50 Values ◽  
Ellman’S Method

Background: Hydrazide-hydrazones have been known as scaffold with various biological activities including inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE). Cholinesterase inhibitors are mainstays of dementias’ treatment. Objective: Twenty-five iodinated hydrazide-hydrazones and their analogues were designed as potential central AChE and BuChE inhibitors. Methods: Hydrazide-hydrazones were synthesized from 4-substituted benzohydrazides and 2-/4- hydroxy-3,5-diiodobenzaldehydes. The compounds were investigated in vitro for their potency to inhibit AChE from electric eel and BuChE from equine serum using Ellman’s method. We calculated also physicochemical and structural parameters for CNS delivery. Results: The derivatives exhibited a moderate dual inhibition with IC50 values ranging from 15.1-140.5 and 35.5 to 170.5 μmol.L-1 for AChE and BuChE, respectively. Generally, the compounds produced a balanced or more potent inhibition of AChE. N'-[(E)-(4-Hydroxy-3,5-diiodophenyl)methylidene]-4- nitrobenzohydrazide 2k and 4-fluoro-N'-(2-hydroxy-3,5-diiodobenzyl)benzohydrazide 3a were the most potent inhibitors of AChE and BuChE, respectively. Structure-activity relationships were established, and molecular docking studies confirmed interaction with enzymes. Conclusion: Many novel hydrazide-hydrazones showed lower IC50 values than rivastigmine against AChE and some of them were comparable for BuChE to this drug used for the treatment of dementia. They interact with cholinesterases via non-covalent binding into the active site. Based on the BOILEDEgg approach, the majority of the derivatives met the criteria for blood-brain-barrier permeability.

Evaluation of Pyrano[3,2 C] Quinoline Analogues as Anticancer Agents

2019 ◽  
Vol 19 (10) ◽  
pp. 1285-1292 ◽  
Author(s):  
Kuldip D. Upadhyay ◽  
Anamik K. Shah
Keyword(s):  
Anticancer Agents ◽  
Human Cancer ◽  
Biological Activities ◽  
Cytotoxic Agents ◽  
Tumor Growth Inhibition ◽  
Mice Model ◽  
One Pot ◽  
Aryl Ring ◽  
Hct 116

Background: Quinoline analogues exhibited diversified biological activities depending on the structure type. A number of natural products with pyrano[3,2-c]quinolone structural motifs and patented chromenes were reported as promising cytotoxic agents. Objective: The present study is aimed to evaluate a new series of pyrano[3,2-c]quinoline scaffolds derived from the fusion of bioactive quinolone pharmacophore with structurally diverse aryl substituted chromene for its cytotoxicity. Methods: A library of pyrano[3,2-c]quinoline analogues was prepared from one-pot multi component synthesis using various aromatic aldehydes, malononitrile and 2,4-dihydroxy-1-methylquinoline. The new synthetics were primarily screened for its cytotoxicity (IC50) against different human cancer cell lines in vitro. The promising synthetics were further evaluated in vitro for their potency against different kinase activity. The promising compounds were finally tested for their in vivo efficacy in SCID type mice HCT-116 tumor model. Results: The screening results revealed that compounds 4c, 4f, 4i and 4j showed promising activity in in vitro study. However, compound 4c was found to be the most potent candidate with 23% tumor growth inhibition in HCT-116 tumor mice model. Conclusion: The structure activity relationship suggested that 3-substitution on the aryl ring at C4 position of the pyrano[3,2 c]quinolone moiety seems to have an important position for cytotoxicity activity. However, 3- chloro substitution at C4 aryl ring showed a significant alteration of the bioactive conformer of the parent scaffold and outcome with compound 4c as the most potent candidate of the series.

scholarly journals A new series of 2,4-thiazolidinediones endowed with potent aldose reductase inhibitory activity

2021 ◽  
Vol 19 (1) ◽  
pp. 347-357
Author(s):  
Belgin Sever ◽  
Mehlika Dilek Altıntop ◽  
Yeliz Demir ◽  
Cüneyt Türkeş ◽  
Kaan Özbaş ◽  
...  
Keyword(s):  
Aldose Reductase ◽  
In Silico ◽  
Aromatic Aldehydes ◽  
Docking Studies ◽  
Mouse Fibroblast ◽  
L929 Mouse Fibroblast ◽  
Orally Bioavailable ◽  
L929 Mouse ◽  
Solvent Free Reaction

Abstract In an effort to identify potent aldose reductase (AR) inhibitors, 5-(arylidene)thiazolidine-2,4-diones (1–8), which were prepared by the solvent-free reaction of 2,4-thiazolidinedione with aromatic aldehydes in the presence of urea, were examined for their in vitro AR inhibitory activities and cytotoxicity. 5-(2-Hydroxy-3-methylbenzylidene)thiazolidine-2,4-dione (3) was the most potent AR inhibitor in this series, exerting uncompetitive inhibition with a K i value of 0.445 ± 0.013 µM. The IC50 value of compound 3 for L929 mouse fibroblast cells was determined as 8.9 ± 0.66 µM, pointing out its safety as an AR inhibitor. Molecular docking studies suggested that compound 3 exhibited good affinity to the binding site of AR (PDB ID: 4JIR). Based upon in silico absorption, distribution, metabolism, and excretion data, the compound is predicted to have favorable pharmacokinetic features. Taking into account the in silico and in vitro data, compound 3 stands out as a potential orally bioavailable AR inhibitor for the management of diabetic complications as well as nondiabetic diseases.

scholarly journals Kinase Inhibitors of Novel Pyridopyrimidinone Candidates: Synthesis and In Vitro Anticancer Properties

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Nagy M. Khalifa ◽  
Mohamed A. Al-Omar ◽  
Hamad M. Alkahtani ◽  
Ahmed H. Bakheit
Keyword(s):  
Kinase Inhibitors ◽  
Human Cancer ◽  
Ethyl Cyanoacetate ◽  
Diethyl Malonate ◽  
Aromatic Aldehydes ◽  
Docking Studies ◽  
Braf V600e ◽  
Kinase Assay ◽  
Human Cancer Cell Lines

A new class of pyridopyrimidinone compounds containing different nitrogenous heterocycles were synthesized starting from the key precursor 2-hydrazinyl-5-phenyl-7-(pyridin-3-yl)pyrido[2,3-d]pyrimidin-4(3H)-one via condensation with series of aromatic aldehydes and cyclization using different reagents as ethyl acetoacetate, ethyl cyanoacetate, diethyl malonate, and ammonium isothiocyanate. The bioassay results showed compound 6 to be highly effective towards three human cancer cell lines (HepG2, PC-3, and HCT-116) in vitro with promising activity values (IC50: 0.5 μM) relative to the standard doxorubicin (IC50: 0.6 μM). Kinase inhibitory evaluation of compound 6 displays hopeful inhibitory action against BRAF V600E, EGFR, and PDGFRβ at100 μM. The molecular docking studies supported the initial kinase assay.

scholarly journals 4-Aminobenzoic Acid Derivatives: Converting Folate Precursor to Antimicrobial and Cytotoxic Agents

Biomolecules ◽  
2019 ◽  
Vol 10 (1) ◽  
pp. 9 ◽  
Author(s):  
Martin Krátký ◽  
Klára Konečná ◽  
Jiří Janoušek ◽  
Michaela Brablíková ◽  
Ondřej Janďourek ◽  
...  
Keyword(s):  
Schiff Bases ◽  
Biological Activities ◽  
Aromatic Aldehydes ◽  
Antimycobacterial Activity ◽  
Cytotoxic Agents ◽  
Aminobenzoic Acid ◽  
Human Pathogens ◽  
Essential Nutrient ◽  
One Step ◽  
Imine Bond

4-aminobenzoic acid (PABA), an essential nutrient for many human pathogens, but dispensable for humans, and its derivatives have exhibited various biological activities. In this study, we combined two pharmacophores using a molecular hybridization approach: this vitamin-like molecule and various aromatic aldehydes, including salicylaldehydes and 5-nitrofurfural, via imine bond in one-step reaction. Resulting Schiff bases were screened as potential antimicrobial and cytotoxic agents. The simple chemical modification of non-toxic PABA resulted in constitution of antibacterial activity including inhibition of methicillin-resistant Staphylococcus aureus (minimum inhibitory concentrations, MIC, from 15.62 µM), moderate antimycobacterial activity (MIC ≥ 62.5 µM) and potent broad-spectrum antifungal properties (MIC of ≥ 7.81 µM). Some of the Schiff bases also exhibited notable cytotoxicity for cancer HepG2 cell line (IC50 ≥ 15.0 µM). Regarding aldehyde used for the derivatization of PABA, it is possible to tune up the particular activities and obtain derivatives with promising bioactivities.

Cytotoxic and Genotoxic Activities of Alkaloids from the Bulbs of Griffinia gardneriana and Habranthus itaobinus (Amaryllidaceae)

2019 ◽  
Vol 19 (5) ◽  
pp. 707-717 ◽  
Author(s):  
Eduardo R. Cole ◽  
Jean P. de Andrade ◽  
João F. Allochio Filho ◽  
Elisângela F. P. Schmitt ◽  
Anderson Alves-Araújo ◽  
...  
Keyword(s):  
Cell Lines ◽  
Caspase 3 ◽  
Biological Activities ◽  
Docking Studies ◽  
In Vitro Cytotoxicity ◽  
Cytotoxic Activities ◽  
Isolation And Identification ◽  
Wide Range

Background: Amaryllidaceae plants are known to be a great source of alkaloids, which are considered an extensive group of compounds encompassing a wide range of biological activities. The remarkable cytotoxic activities observed in most of the Amaryllidaceae alkaloids derivatives have prompt the chemical and biological investigations in unexplored species from Brazil. Objective: To evaluate the cytotoxic and genotoxic properties of alkaloids of Griffinia gardneriana and Habranthus itaobinus bulbs and study the role of caspase-3 as a molecular apoptosis mediator. Methods: Methanolic crude extracts of Griffinia gardneriana and Habranthus itaobinus bulbs were submitted to acid-base extraction to obtain alkaloid-enriched fractions. The obtained fractions were fractionated using chromatographic techniques leading to isolation and identification of some alkaloids accomplished via HPLC and 1H-NMR, respectively. Molecular docking studies assessed the amount of free binding energy between the isolated alkaloids with the caspase-3 protein and also calculated the theoretical value of Ki. Studies have also been developed to evaluate in vitro cytotoxicity and genotoxicity in such alkaloids and apoptosis activation via the caspase pathway using both tumor and normal cell lines. Results: Seven alkaloids were isolated and identified. Among these, 11-hydroxyvittatine and 2-α-7- dimethoxyhomolycorine were not cytotoxic, whereas tazettine, trisphaeridine, and sanguinine only showed activity against the fibroblast lineage. Lycorine and pretazettine were 10 to 30 folds more cytotoxic than the other alkaloids, including cancerous lines, and were genotoxic and capable of promoting apoptosis via the caspase-3 pathway. This result supports data obtained in docking studies wherein these two compounds exhibited the highest free energy values. Conclusion: The cytotoxicity assay revealed that, among the seven alkaloids isolated, only lycorine and pretazettine were active against different cell lines, exhibiting concentration- and time-dependent cytotoxic actions alongside genotoxic action and the ability to induce apoptosis by caspase-3, a result consistent with those obtained in docking studies.

Pharmacogenetics of a PARP inhibitor ABT-888 metabolic pathway

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14556-e14556
Author(s):  
J. Li ◽  
X. Sha ◽  
P. LoRusso
Keyword(s):  
Metabolic Pathway ◽  
Genetic Variants ◽  
Parp Inhibitor ◽  
Liver Microsomes ◽  
Therapeutic Outcome ◽  
Cytotoxic Agents ◽  
Wild Type ◽  
Metabolite Formation ◽  
Drug Concentrations

e14556 Background: Poly(ADP-ribose) polymerase (PARP) is essential for single-stranded DNA break repair and repair of DNA damage can lead to radio- and chemo-resistance. Thus, inhibition of PARP activity can sensitize cells to cytotoxic therapies. ABT-888 is a potent, orally bioavailable PARP inhibitor. Preclinical studies suggest that ABT-888 potentiates multiple cytotoxic agents and its efficacy is correlated with plasma/tumor drug concentrations. The objective of this study was to determine the pharmacogenetic effect of genetic variants in the ABT-888 metabolic pathway, with the aim to better understand molecular basis of the variation in ABT-888 pharmacokinetics (PK) and therapeutic outcome. Methods: The major enzymes responsible for ABT-888 metabolism were identified by in vitro metabolism studies with specific recombinant human cytochrome P450 (CYP) enzymes. The functional significance of genetic variants of the identified enzymes was assessed by examining ABT-888 metabolic kinetics by candidate variant enzymes and microsomes. The association of the functional significant genetic variants with the PK and clinical outcome is being evaluated in the context of an ongoing phase I trial in which ABT-888 is administered in combination with irinotecan in patients with advanced solid tumors. Results: ABT-888 was metabolized predominantly by human CYP2D6, to a less extent by CYP1A1, and to a negligible extent by CYP1A2, 2C9, 2C19, 3A4, and 3A5. CYP2D6*10 exhibited markedly reduced catalytic capability in ABT-888 overall metabolism and the metabolite (A-925088) formation, with in vitro maximum clearance being 31% and 5.3%, respectively, of that estimated from the wild-type CYP2D6. In human liver microsomes carrying homozygous CYP2D6*4, the rates of parent drug disappearance and metabolite formation were significantly lower than those observed in the microsomes carrying wild-type CYP2D6, P < 0.05. Conclusions: CYP2D6 is the predominant enzyme responsible for the hepatic metabolism of ABT-888. Common allelic variants CYP2D6*10 and *4 are associated with significantly reduced metabolic activity towards ABT-888. CYP2D6 polymorphisms may influence the PK and therapeutic outcome of ABT-888. Its clinical relevance remains to be determined. No significant financial relationships to disclose.

scholarly journals Pyrazole Incorporated New Thiosemicarbazones: Design, Synthesis and Investigation of DPP-4 Inhibitory Effects

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5003
Author(s):  
Belgin Sever ◽  
Hasan Soybir ◽  
Şennur Görgülü ◽  
Zerrin Cantürk ◽  
Mehlika Dilek Altıntop
Keyword(s):  
Cell Line ◽  
Aromatic Aldehydes ◽  
Docking Studies ◽  
Phenyl Isothiocyanate ◽  
Inhibitory Effects ◽  
Dipeptidyl Peptidase 4 ◽  
Ic50 Value ◽  
In Silico Studies ◽  
Nih 3T3

Dipeptidyl peptidase-4 (DPP-4) inhibition has been recognized as a promising approach to develop safe and potent antidiabetic agents for the management of type 2 diabetes. In this context, new thiosemicarbazones (2a–o) were prepared efficiently by the reaction of aromatic aldehydes with 4-[4-(1H-pyrazol-1-yl)phenyl]thiosemicarbazide (1), which was obtained via the reaction of 4-(1H-pyrazol-1-yl)phenyl isothiocyanate with hydrazine hydrate. Compounds 2a–o were evaluated for their DPP-4 inhibitory effects based on a convenient fluorescence-based assay. 4-[4-(1H-pyrazol-1-yl)phenyl]-1-(4-bromobenzylidene)thiosemicarbazide (2f) was identified as the most effective DPP-4 inhibitor in this series with an IC50 value of 1.266 ± 0.264 nM when compared with sitagliptin (IC50 = 4.380 ± 0.319 nM). MTT test was carried out to assess the cytotoxic effects of compounds 2a–o on NIH/3T3 mouse embryonic fibroblast (normal) cell line. According to cytotoxicity assay, compound 2f showed cytotoxicity towards NIH/3T3 cell line with an IC50 value higher than 500 µM pointing out its favourable safety profile. Molecular docking studies indicated that compound 2f presented π-π interactions with Arg358 and Tyr666 via pyrazole scaffold and 4-bromophenyl substituent, respectively. Overall, in vitro and in silico studies put emphasis on that compound 2f attracts a great notice as a drug-like DPP-4 inhibitor for further antidiabetic research.

scholarly journals Synthesis and Biological Evaluation of Alanine Derived Bioactive p-Toluenesulphonamide Analogs

2020 ◽  
Vol 11 (4) ◽  
pp. 6449-6458
Author(s):  
Melford C Egbujor ◽  
Uchechukwu C Okoro ◽  
Samuel A Egu ◽  
Pius I Egwuatu ◽  
Florence U Eze ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Antimalarial Activity ◽  
Biological Activities ◽  
Analytical Data ◽  
Antioxidant Properties ◽  
Antimicrobial Properties ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Agar Dilution

Sulphonamides and carboxamides have great pharmacological importance. The purpose of the study was to synthesize alanine-derived bioactive sulphonamides bearing carboxamides and evaluate their biological activities. The reaction of p-toluenesulphonyl chloride with L-alanine afforded compound 1, which was acetylated to obtain compound 2. The chlorination and ammonolysis of compound 2 gave the carboxamide backbone (3) which was coupled with aryl/heteroaryl halides to afford the hybrid compounds 4, 5 and 6. Structures were confirmed by FTIR, 1H-NMR, 13C-NMR spectra and elemental analytical data. The in vitro antimicrobial properties were determined by agar dilution, and the antioxidant properties were also investigated. Molecular docking interactions of the analogues were determined using PyRx. Compounds 4, 5 and 6 exhibited excellent in vitro antimicrobial properties in the range of 0.5-1.0mg/ml while compounds 1and 2 had half-maximal inhibitory concentration (IC50) of 1.11±0.15µg/ml and 1.12±0.13µg/ml respectively. For the molecular docking studies, compounds 5 and 6 displayed the best antitrypanosomal activity with binding affinities of -13.95 and -13.51kcal/mol respectively while compound 4 showed the highest in silico antimalarial activity having binding affinity of -11.95kcal/mol. All the alanine derived sulphonamides were observed to be potential antimicrobial, antioxidant, antitrypanosomal and antimalarial agents following the biological activities studies.

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