2,4-Disubstituted Quinazoline Derivatives Act as Inducers of Tubulin Polymerization: Synthesis and Cytotoxicity

2019 ◽  
Vol 19 (8) ◽  
pp. 1048-1057 ◽  
Author(s):  
Ebrahim S. Moghadam ◽  
Maryam H. Tehrani ◽  
René Csuk ◽  
Lucie Fischer ◽  
Mohammad Ali Faramarzi ◽  
...  
Keyword(s):  
Human Tumor ◽  
Cancer Drug ◽  
Tubulin Polymerization ◽  
Highly Active ◽  
Cancer Drug Resistance ◽  
Antimitotic Drugs ◽  
Molecular Modelling Studies ◽  
Ic50 Values ◽  
Modelling Studies ◽  
Quinazoline Derivatives

Background: During last recent years number of anti-tubulin agents were introduced for treatment of diverse kind of cancer. Despite of their potential in treatment of cancer, drug resistance and adverse toxicity such as peripheral neuropathy are some of the negative criteria of anti-tubulin agents. Methods: Twenty seven quinazoline derivatives were synthesized using a multicomponent reaction. The cytotoxicity of compounds 1-27 was tested in SRB assays employing five different human tumor cell lines. Effect of two of active compounds on tubulin polymerization was also checked using a commercially available assay kit. Molecular modelling studies were also performed using autodock tools software. Results: SRB assays showed that compounds 2, 9, 16 and 26, being highly cytotoxic with IC50 values ranging between 2.1 and 14.3µM. The possible mode of action of compounds, 2, 9, 16 and 26, and the taxol binding site of the protein tubulin, an important goal for antimitotic drugs, was also studied by molecular docking, which showed reasonable interactions with tubulin active site, followed by investigation of the effects of compounds 9 and 16 on the polymerization of tubulin. The results showed the tested compounds to be highly active as inducers of tubulin polymerization. Conclusion: Altogether, with respect to obtained results, it is attractive and beneficial to further investigation on quinazoline scaffold as antimitotic agents.

Design, Synthesis and In Vitro Evaluation of 2-Oxo-N-substituted Phenyl- 2H-chromene-3-carboxamide Derivatives as HIV Integrase Strand Transfer Inhibitors

2020 ◽  
Vol 17 (4) ◽  
pp. 418-427
Author(s):  
Pankaj Wadhwa ◽  
Priti Jain ◽  
Hemant R. Jadhav
Keyword(s):  
Diethyl Malonate ◽  
Significant Inhibition ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Design Synthesis ◽  
Molecular Modelling Studies ◽  
Ic50 Values ◽  
Modelling Studies ◽  
Hiv 1

Background: A series of eighteen 2-Oxo-N-substituted phenyl- 2H-chromene-3- carboxamide analogues has been evaluated for HIV-1 integrase (IN) inhibition. Methods: The derivatives were synthesized via a two-step pathway commencing with 2- hydroxybenzaldehyde and diethyl malonate followed by hydrolysis of ester and coupling with various aromatic amines. The HIV-1 IN inhibitory potential of these compounds has been studied relative to dolutegravir, a known HIV-1 IN inhibitor using a standard available kit. Results: Six molecules (compounds 13h, 13i, 13l, 13p to 13r) showed significant inhibition of HIV- 1 integrase 3′-strand transfer with IC50 values less than 1.7 μM. The presence of chromene-3- carboxamide motif was shown to be crucial for the enzymatic activity. In addition, molecular modelling studies were also done to justify the IN inhibition and in vitro-in silico correlation was drawn. Conclusion: However, these compounds did not show HIV-1 and HIV-2 inhibition below their cytotoxic concentration indicating that these compounds cannot be taken further for anti-HIV activity as such and require structural modification.

scholarly journals Molecular Modelling Studies on Pyrazole Derivatives for the Design of Potent Rearranged during Transfection Kinase Inhibitors

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 691
Author(s):  
Swapnil P. Bhujbal ◽  
Seketoulie Keretsu ◽  
Seung Joo Cho
Keyword(s):  
Molecular Modelling ◽  
Active Compound ◽  
Kinase Inhibitors ◽  
Human Cancer ◽  
Structural Characteristics ◽  
Dynamics Simulation ◽  
Cancer Drug ◽  
Energy Calculation ◽  
Molecular Modelling Studies ◽  
Modelling Studies

RET (rearranged during transfection) kinase, one of the receptor tyrosine kinases, plays a crucial role in the development of the human nervous system. It is also involved in various cell signaling networks responsible for the normal cell division, growth, migration, and survival. Previously reported clinical studies revealed that deregulation or aberrant activation of RET signaling can cause several types of human cancer. For example, medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia (MEN2A, MEN2B) occur due to sporadic mutation or germline RET mutation. A number of RET kinase inhibitors have been approved by the FDA for the treatment of cancer, such as cabozantinib, vandetanib, lenvatinib, and sorafenib. However, each of these drugs is a multikinase inhibitor. Hence, RET is an important therapeutic target for cancer drug design. In this work, we have performed various molecular modelling studies, such as molecular docking and dynamics simulation for the most active compound of the pyrazole series as RET kinase inhibitors. Furthermore, molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) free energy calculation and 3-dimensional quantitative structure–activity relationship (3D-QSAR) were performed using g_mmpbsa and SYBYL-X 2.1 package. The results of this study revealed the crucial binding site residues at the active site of RET kinase and contour map analysis showed important structural characteristics for the design of new highly active inhibitors. Therefore, we have designed ten RET kinase inhibitors, which showed higher inhibitory activity than the most active compound of the series. The results of our study provide insights to design more potent and selective RET kinase inhibitors.

Synthesis of Novel Pyrido[2′, 3′:3,4]Pyrazolo[1, 5‐ a ]Quinazoline Derivatives, Their Biological Evaluation and Molecular Modelling Studies

2018 ◽  
Vol 3 (27) ◽  
pp. 7813-7821 ◽  
Author(s):  
Nagiri Ravi Kumar ◽  
Desireddy Krishna Swaroop ◽  
Nagender Punna ◽  
Kanugala Sirisha ◽  
Thipparapu Ganapathi ◽  
...  
Keyword(s):  
Molecular Modelling ◽  
Biological Evaluation ◽  
Molecular Modelling Studies ◽  
Modelling Studies ◽  
Quinazoline Derivatives

Molecular modelling studies on thiazole-based α-Glucosidase Inhibitor using docking and CoMFA, CoMSIA and HQSAR

2020 ◽  
Vol 17 ◽  
Author(s):  
Deshbandhu Joshi ◽  
Shourya Yadav ◽  
Rajesh Sharma ◽  
Mitrunjaya Pandya ◽  
Raghvendra Singh Bhadauria
Keyword(s):  
Correlation Coefficient ◽  
Training Set ◽  
Glucosidase Inhibitors ◽  
Biological Dataset ◽  
Donor And Acceptor ◽  
Molecular Modelling Studies ◽  
Ic50 Values ◽  
Modelling Studies ◽  
Standard Error Estimation ◽  
Leave One Out

Aims and Objective: The biological dataset was retrieved from two series of α-glucosidase inhibitors synthesized by Rahim et al. and Taha et al. and consisted of a total 46 (forty-six) α-glucosidase inhibitors. Methods: The α-glucosidase inhibitory IC50 values (µM; performed against α-glucosidase from Saccharomyces cerevisiae) were converted into negative logarithmic units (pIC50). The CoMFA and CoMSIA models were created utilizing 37 as the training set and externally validated utilizing 9 as a test set. The CoMFA models MMFF94 were generated and ranging from 3.4661 to 5.2749 using leave-one-out PLS analysis cross-validated correlation coefficient q2 0.787 a high non-crossvalidated correlation coefficient r2 0.819 with a low standard error estimation (SEE) 0.041, F value 1316.074 and r2pred 0.996. Results: The steric and electrostatic fields contributions were 0.507 and 0.493, respectively. The CoMSIA model q2 0.805, r 2 0.833 was attained, (SEE) 0.065, F value 520.302 and r2pred 0.990. Contribution of steric, electrostatic, hydrophobic, donor and acceptor fields were 0.151, 0.268, 0.223, 0.234, 0.124 respectively. Conclusion: The HQSAR model of training set exhibits significant cross-validated correlation coefficient q2 0.800 and noncross-validated correlation coefficient r2 0.943.

scholarly journals Development of New Multicomponent Reactions in Eco-Friendly Media-Greener Reaction and Expeditious Synthesis of Novel Bioactive Benzylpyranocoumarins

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Hamida Jelali ◽  
A. Chakchouk-Mtibaa ◽  
Lasaad Baklouti ◽  
Hallouma Bilel ◽  
Yaser Bathich ◽  
...  
Keyword(s):  
Density Functional ◽  
Aromatic Aldehydes ◽  
Density Functional Theory Calculations ◽  
Butylated Hydroxytoluene ◽  
Dilution Method ◽  
Coumarin Derivatives ◽  
H Nmr ◽  
Molecular Modelling Studies ◽  
Ic50 Values ◽  
Modelling Studies

Multicomponent cyclocondensation of hydrazine derivatives, ethyl acetoacetate, aromatic aldehydes, and 4-hydroxycoumarin has been reported. The optimization details of the developed novel protocol are recorded. The novel procedure features short reaction time, moderate yields, and simple workup. In addition, BMIM[triflate] was chosen as a green solvent. The structures of the obtained benzylpyrazolyl coumarins were determined and confirmed by 1H NMR, 13C NMR, IR, and elemental analysis. The MIC values of benzylpyrazolyl coumarin derivatives were determined by the microbroth dilution method using 96-well plates. However, the derivatives 5a, 5b, 5d, and 5g possess the strongest activities. Compound 5b was the most active derivative against Candida albicans. Moreover, the antioxidant activity determination of these coumarins derivatives 5(a–g)–6(a–g) were studied with the DPPH and compared with gallic acid (GA)and butylated hydroxytoluene (BHT). Molecular modelling studies using DFT (density functional theory) calculations showed that there two tautomers A and B in which A is more stable than B. The benzylpyrazolyl coumarin derivatives 5e and 6f exhibited the most cytotoxic effect on the promising cytotoxic activity with IC50 values 4.45 μg/mL against MDA-MB-231 and 4.85 μg/mL against MCF7, respectively.

Fanconi Anemia DNA Repair Pathway as a New Mechanism to Exploit Cancer Drug Resistance

2020 ◽  
Vol 20 (9) ◽  
pp. 779-787
Author(s):  
Kajal Ghosal ◽  
Christian Agatemor ◽  
Richard I. Han ◽  
Amy T. Ku ◽  
Sabu Thomas ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Cancer Drug ◽  
Drug Resistant ◽  
Cancer Drugs ◽  
Repair Pathway ◽  
Cancer Drug Resistance ◽  
Anti Cancer ◽  
Cancerous Cells

Chemotherapy employs anti-cancer drugs to stop the growth of cancerous cells, but one common obstacle to the success is the development of chemoresistance, which leads to failure of the previously effective anti-cancer drugs. Resistance arises from different mechanistic pathways, and in this critical review, we focus on the Fanconi Anemia (FA) pathway in chemoresistance. This pathway has yet to be intensively researched by mainstream cancer researchers. This review aims to inspire a new thrust toward the contribution of the FA pathway to drug resistance in cancer. We believe an indepth understanding of this pathway will open new frontiers to effectively treat drug-resistant cancer.

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