QSAR and Molecular Docking Studies on a Series of Cinnamic Acid Analogues as Epidermal Growth Factor Receptor (EGFR) Inhibitors (original) (raw)
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Bioorganic & Medicinal Chemistry, 2011
A novel type of cinnamic acid quinazoline amide derivatives (20-42), which designed the combination between quinazoline as the backbone and various substituted cinnamic acid as the side chain, have been synthesized and their biological activities were evaluated within cytotoxicity assay firstly and then potent EGFR inhibitory activity. Compound 42 demonstrated the most potent inhibitory activity (IC 50 = 0.94 lM for EGFR), which could be optimized as a potential EGFR inhibitor in the further study. Docking simulation was performed to position compound 42 into the EGFR active site to determine the probable binding model. Analysis of the binding conformation of 42 in active site displayed compound 42 was stabilized by hydrogen bonding interactions with Lys822, which was different from other derivatives. In the further study, Compounds 43 and 44 had been synthesized and their biological activities were also evaluated, which were the same as that we expected. Compound 43 has demonstrated significant EGFR (IC 50 = 0.12 lM) and tumor growth inhibitory activity as a potential anticancer agent.
Molecular Docking Compounds of Cinnamaldehyde Derivatives as Anticancer Agents
Asian Pacific Journal of Cancer Prevention
Objective: Cinnamaldehyde (CM) has a molecular structure with the main reaction center of an aromatic ring which the bioactivity can be modified as an anticancer agent by substituting the groups in the ortho (o), meta (m), and para (p) position. The present study aimed to investigate the correlation of the cluster region that was substituted in CM on its activity for various anticancer receptors. Methods: The receptor types used in the test were 5FL6, 1HOV, 4GY7, 5EAM, 4XCU, 4EL9, and 4PQW. The suitability of the hydroxy (OH) and methoxy (OMe) groups, which were substituted, was studied based on the value of Ki, their interactions with metal cofactors, and the type of amino acid residues that function as cancer receptor inhibitors. The docking was conducted using AutoDock 4. Results: The study results showed that all derivative compounds (o, m, and p)-OH and-OMe CM commonly had better anticancer activities than CM. o-OH CM has the best activity against receptors 5FL6, 1HOV, 4GY7, 5EAM, and 4XCU, and m-OMe CM has better activity against the 4EL9 receptors when compared with other CM derivatives. Conclusion: Based on this study, the compound derived from CM, i.e. OHC, tends to show the best anticancer activity.
Cinnamic acids have been identified as interesting compounds with antioxidant, anti-inflammatory and cytotoxic properties. In the present study, simple cinnamic acids were synthesized by Knoevenagel condensation reactions and evaluated for the above biological activities. Compound 4ii proved to be the most potent LOX inhibitor. Phenyl-substituted acids showed better inhibitory activity against soybean LOX, and it must be noted that compounds 4i and 3i with higher lipophilicity values resulted less active than compounds 2i and 1i. The compounds have shown very good activity in different antioxidant assays. The antitumor properties of these derivatives have been assessed by their 1/IC 50 inhibitory values in the proliferation of HT-29, A-549, OAW-42, MDA-MB-231, HeLa and MRC-5 normal cell lines. The compounds presented low antitumor activity considering the IC 50 values attained for the cell lines, with the exception of compound 4ii. Molecular docking studies were carried out on cinnamic acid derivative 4ii and were found to be in accordance with our experimental biological results.
Molecules (Basel, Switzerland), 2014
Cinnamic acids have been identified as interesting compounds with antioxidant, anti-inflammatory and cytotoxic properties. In the present study, simple cinnamic acids were synthesized by Knoevenagel condensation reactions and evaluated for the above biological activities. Compound 4ii proved to be the most potent LOX inhibitor. Phenyl- substituted acids showed better inhibitory activity against soybean LOX, and it must be noted that compounds 4i and 3i with higher lipophilicity values resulted less active than compounds 2i and 1i. The compounds have shown very good activity in different antioxidant assays. The antitumor properties of these derivatives have been assessed by their 1/IC50 inhibitory values in the proliferation of HT-29, A-549, OAW-42, MDA-MB-231, HeLa and MRC-5 normal cell lines. The compounds presented low antitumor activity considering the IC50 values attained for the cell lines, with the exception of compound 4ii. Molecular docking studies were carried out on cinnam...
Innovare Journal of Life Science, 2023
Objective: The pathology of every disease passes through the inflammation stage; hence, the design and optimization of potential lead compounds as anti-inflammatory agents is still a significant part of medicinal chemistry globally. Methods: In this study, we designed, synthesized, and characterized some cinnamic acid derivatives and performed molecular docking of the derivatives on the human cyclooxygenase-1 (COX-1) enzyme. Results: The elemental analysis showed the presence of different functional groups. Molecular docking was performed on the active sites of COX-1 (PDB ID: 6Y3C). The derivatives as well as the standard compound, were observed to interact mainly with the arginine residue of the target protein. The dioxomethylene substituted derivative showed the highest binding affinity, compared with other derivatives, including the standard drug (−6.8 kcal/mol). Conclusion: The binding affinity observed in the cinnamic derivatives, and biological activities correlations revealed that compounds with the dioxomethylene group would be good anti-inflammatory lead molecules, as they demonstrated high affinity to the target protein and biological activities. Thus, these compounds can serve as potential lead compounds for the design, and development of effective anti-inflammatory agents, targeted to inhibit the human COX-1 enzyme involved in biological inflammatory mechanisms.
Molecules
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains one of the top ten causes of death worldwide and the main cause of mortality from a single infectious agent. The upsurge of multi- and extensively-drug resistant tuberculosis cases calls for an urgent need to develop new and more effective antitubercular drugs. As the cinnamoyl scaffold is a privileged and important pharmacophore in medicinal chemistry, some studies were conducted to find novel cinnamic acid derivatives (CAD) potentially active against tuberculosis. In this context, we have engaged in the setting up of a quantitative structure–activity relationships (QSAR) strategy to: (i) derive through multiple linear regression analysis a statistically significant model to describe the antitubercular activity of CAD towards wild-type Mtb; and (ii) identify the most relevant properties with an impact on the antitubercular behavior of those derivatives. The best-found model involved only geometrical and electronic CA...
Structure−Antifungal Activity Relationship of Cinnamic Acid Derivatives
Journal of Agricultural and Food Chemistry, 2007
A structure-antifungal activity relationship (SAR) study of 22 related cinnamic acid derivatives was carried out. Attention was focused on the antifungal activities exhibited against Aspergillus flavus, Aspergillus terreus, and Aspergillus niger. (E)-3-(4-Methoxy-3-(3-methylbut-2-enyl)phenyl)acrylic acid (16) exhibited antifungal activity against A. niger, comparable to that of miconazole and a significant antifungal effect against A. flavus and A. terreus as well. A structure-activity relationship (SAR) study of related cinnamic acid derivatives has allowed a model to be proposed for the recognition of the minimal structural requirements for the antifungal effect in this series.
European journal of …, 2004
A series of esters (I a-k ), substituted derivatives (II a-d ) and amides (III a-q ) of cinnamic acid were synthesized and evaluated as antibacterial and antifungal agents. All the derivatives belonging to the series I, II and III showed antimicrobial activity comparable to the standard. Compounds I f and II c proved to be the most effective compounds. Quantitative structure-activity relationship (QSAR) investigation with multiple linear regression analysis was applied to find a correlation between different calculated physicochemical parameters of the compounds and biological activity. The quantitative models relating the structural features of cinnamic acid derivatives I a-k , II a-d and III a-q and their antimicrobial activity showed that Gram negative Escherichia coli and Candida albicans (fungus) were the most sensitive microorganisms.
Journal of Applied Pharmaceutical Science, 2017
After over half a century of chemotherapy research, cancer has remained as one of the most life-threatening diseases to treat. In the present study, a series of phthalazine derivatives as anticancer agent was examined to determine the structural requirement for epidermal growth factor receptor (EGFR) inhibition by threedimensional quantitative structural activity relationship (3D-QSAR) using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. Evaluation of 20 compounds (training set) served to establish model, which was validated by evaluation of a set of 08 compounds (test set). The lowest energy conformer of the most active molecule obtained from the systematic search was used as the template structure for alignment of data set. The optimum partial least square analysis (PLS) for CoMFA and CoMSIA models exhibited good 'leave-one-out' cross-validated coefficient (q 2) of 0.736 and 0.806, the coefficient of determination (r 2) of 0.964 and 0.976 and good predictive power of (r 2 pred) of 0.826 and 0.792 respectively. Docking was carried out to identify mode of interaction with EGFR. The final model of QSAR along with information assembled from contour maps and docking study may be used for design ing novel phthalazine derivatives as potent anticancer agents.