Discovery of Substituted 2-oxoquinolinylthiazolidin-4-one Analogues as Potential EGFRK Inhibitors in Lung Cancer Treatment

Abstract

Purpose Cancer is the second leading cause of death globally and is responsible for an estimated 9.6 million deaths in 2018. Globally, about 1 in 6 deaths is due to cancer and the chemotherapeutic drugs available have high toxicity and have reported side effects hence, there is a need for the synthesis of novel drugs in the treatment of cancer.

Methods The current research work dealt with the synthesis of a series of 3-(3-acetyl-2-oxoquinolin-1-(2H)-yl-2-(substitutedphenyl)thiazolidin-4-one (Va-j) derivatives and evaluation of their in-vitro anticancer activity. All the synthesized compounds were satisfactorily characterized by IR and NMR data. Compounds were further evaluated for their in-vitro anticancer activity against A-549 (lung cancer) cell lines. The in-vitro anticancer activity was based upon the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay method.

Results The synthesized compounds exhibited satisfactory anticancer properties against the A-549 cell line. The compound (Vh) showed the highest potency amongst the tested derivatives against the A-549 cell line with IC₅₀ values of 100 µg/ml respectively and was also found to be more potent than Imatinib (150 µg/ml) which was used as a standard drug. Molecular docking studies of the titled compounds (Va-j) were carried out using AutoDock Vina/PyRx software. The synthesized compounds exhibited well-conserved hydrogen bonds with one or more amino acid residues in the active pocket of the EGFRK tyrosine kinase domain (PDB 1m17).

Conclusion Among all the synthesized analogues, the binding affinity of the compound (Vh) was found to be higher than other synthesized derivatives and a molecular dynamics simulation study explored the stability of the docked complex system.

Keywords

quinolin-2-one - thiazolidine - anticancer - lung cancer - docking - molecular dynamics - hydrogen bond - ADMET

Publication History

Received: 01 March 2024

Accepted: 02 April 2024

Article published online:
03 June 2024

• References

• 1 Bajaj P, Mamle Desai S, Dighe P. et al. Synthesis of 4-hydroxy-3-(1-hydroxy-2-(substitutedamino)ethyl)-1-phenyl/methylquinolin-2(1H)-one as anticancer Agents. Asian J Pharm Clin Res 2017; 10: 225-228
• 2 Wang C, Wu Y, Shao J. et al. Clinicopathological variables influencing overall survival, recurrence and post-recurrence survival in resected stage I non-small-cell lung cancer. BMC Cancer. 2020 20. 150
• 3 Sung H, Ferlay J, Siegel RL. et al. Global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71: 209-249
• 4 Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature 2018; 553: 446-454
• 5 Nandi S, Dey R, Samadder A. et al. Natural sourced inhibitors of EGFR, PDGFR, FGFR and VEGFR mediated signaling pathways as potential anticancer agents. Curr Med Chem 2022; 29: 212-234
• 6 Nandi S, Manish C. Bagchi. EGFr, FGFr and PDGFr: Emerging targets for anticancer Drug Design. J Can Res Updates 2016; 5: 99-108
• 7 Bethune G, Bethune D, Ridgway N. et al. Epidermal growth factor receptor (EGFR) in lung cancer: an overview and update. J Thorac Dis 2010; 2: 48-51
• 8 Fu K, Xie F, Wang F. et al. Therapeutic strategies for EGFR-mutated non-small cell lung cancer patients with osimertinib resistance. J Hematol Oncol 2022; 15: 173
• 9 O'Leary C, Gasper H, Sahin KB. et al. Epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). Pharmaceuticals (Basel) 2020; 13: 273
• 10 Naik S, Mamle Desai S, Tari P. et al. Synthesis of 2-mercaptoprimidinylquinolin- 2(1H)-one derivatives as antibacterial and antitubercular agents. Indian J Heterocycl Chem 2015; 25: 55-60
• 11 Lolienkar M, Mamle Desai S, Naik S. et al. Synthesis of isoxazoloquinoli-2-ones and evaluation for their reactivation efficacy against diisopropyl fluorophosphate inhibited acetylcholinesterase. Indian J Heterocycl Chem 2017; 27: 245-248
• 12 Reis M, Mamle Desai S, Naik S. et al. Synthesis and evaluation of 2-(4-methoxy-2-oxo-1-phenyl/methyl-1,2-dihydroquinolin-3-yl)-2-methyl-3-(phenyl/ substitutedphenylamino)thiazolidin-4-one as antibacterial and anticancer agents. Indian J Chem 2016; 55: 1254-1258
• 13 Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65: 55-63
• 14 Palkar MB, Singhai AS, Ronad PM. et al. Synthesis, pharmacological screening and in-silico studies of new class of diclofenac analogues as a promising anti- inflammatory agent. Bioorg Med Chem 2014; 22: 2855-2866
• 15 Dassault Systemes. BIOVIA Discovery Studio Visualizr . Dassault Systemes: San Diego 2020.
• 16 O'Boyle NM, Banck M, James CA. et al. Open Babel: An open chemical toolbox. J Cheminform 2011; 3: 1-14
• 17 Dallakyan S, Olson AJ. Small-molecule library screening by docking with PyRx. Methods Mol Biol 2015; 1263: 243-250
• 18 Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. OPEN. Sci Rep 2017; 7: 42717
• 19 Pires DE, Blundell TL, Ascher DB. pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J Med Chem 2015; 58: 4066-4072
• 20 Luo L, Zhong A, Wang Q. et al. Structure-based pharmacophore modeling, virtual screening, molecular docking, admet, and molecular dynamics (MD) simulation of potential inhibitors of pd-l1 from the library of marine natural products. Mar Drugs 2022; 20: 29
• 21 Rajamanickam R, Mannangatty R, Sampathkumar J. et al. A dft study on the mechanism of the formation of 1,4,2,3-dithiadiazinanes by head-to-head [3 + 3] cyclodimerization of thiocarbonyl s-imides. J Phys Org Chem 2021; 34: 4170
• 22 Snyder HD, Kucukkal TG. Computational chemistry activities with avogadro and orca. J Chem Educ 2021; 98: 1335-1341
• 23 Becke AD. Density-functional exchange-energy approximation with correct asymptotic behavior. Phys Rev A (Coll Park) 1988; 38: 3098
• 24 Lee C, Yang W, Parr RG. Development of the colle-salvetti correlation-energy formula into a function of the electron density. Phys Rev B 1988; 37: 785
• 25 Amer MMK, Abdellattif MH, Mouneir SM. et al. Synthesis, dft calculation, pharmacological evaluation, and catalytic application in the synthesis of diverse pyrano[2,3-c]pyrazole derivatives. Bioorg Chem 2021; 114: 105136
• 26 Kausar T, Nayeem SM. Identification of small molecule inhibitors of alk2: a virtual screening, density functional theory, and molecular dynamics simulations study. J Mol Model 2018; 24: 262
• 27 Elkaeed EB, Yousef RG, Elkady H. et al. Design, synthesis, docking, DFT, MD simulation studies of a new nicotinamide-based derivative: in vitro anticancer and VEGFR-2 inhibitory effects. Molecules 2022; 27: 4606
• 28 Flurry RL. Molecular Orbital Theories of Bonding in Organic Molecules. 1968
• 29 Berman HM, Westbrook J, Feng Z. et al. The Protein Data Bank. Nucleic Acids Res 2000; 28: 235-242
• 30 Stamos J, Sliwkowski MX, Eigenbrot C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. JBC 2002; 277: 46265-46272
• 31 Berman HM, Westbrook J, Feng Z. et al. AutoDock Vina 1.2.0: new docking methods, expanded force field, and python bindings. J Chem Inf Model 2021; 61: 3891-3898
• 32 Forli S, Huey R, Pique ME. et al. Computational protein-ligand docking and virtual drug screening with the Autodock suite. Nat Protoc 2016; 11: 905-919
• 33 Pol-Fachin L, Fernandes CL, Verli H. Performance on the characterization of glycoprotein conformational ensembles through molecular dynamics simulations. Carbohydr Res 2009; 344: 491-500
• 34 WebGro | UAMS https://simlab.uams.edu/ (updated 2022-02-14 accessed 2022-11-24).
• 35 Vishvakarma VK, Pal S, Singh P. et al. Interactions between main protease of sars- cov-2 and testosterone or progesterone using a computational approach. J Mol Struct 2022; 1251: 131965
• 36 Pronk S, Pall S, Schulz R. et al. Gromacs: high-performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 2015; 1-2: 19-25
• 37 Schuttelkopf AW, Van Aalten DMF. PRODRUG: A tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr D Biol Crystallogr 2004; 60: 1355-1363
• 38 Izadi S, Anandakrishnan R, Onufriev AV. Building water models: a different approach. J Phys Chem Lett 2014; 5: 3863-3871
• 39 Gorai S, Junghare V, Kundu K. et al. Synthesis of dihydrobenzofuro[3,2-b]chromenes as potential 3CLpro inhibitors of SARS-CoV-2: A molecular docking and molecular dynamics study. ChemMedChem 2022; 17: 202100782
• 40 Nose S. A molecular dynamics method for simulations in the canonical ensemble. Mol Phys 2002; 100: 191-198
• 41 Alturki NA, Mashraqi MM, Alzamami A. et al. A novel method for molecular dynamics simulation in the isothermal-isobaric ensemble. Mol Phys 2011; 109: 191-202
• 42 Bepari AK, Reza HM. Identification of a novel inhibitor of sars-cov-2 3cl-pro through virtual screening and molecular dynamics simulation. PeerJ 2021; 9: 11261
• 43 Parrinello M, Rahman A. Polymorphic transitions in single crystals: a new molecular dynamics method. J Appl Phys 1981; 52: 7182-7190
• 44 Kushwaha PP, Singh AK, Bansal T. et al. Identification of natural inhibitors against sars-cov-2 drugable targets using molecular docking, molecular dynamics simulation, and mm-pbsa approach. Front cell infect microbiol 2021; 11: 730288
• 45 Hoover WG. Canonical dynamics: equilibrium phase-space distributions. Phys Rev A (Coll Park) 1985; 31: 1695-1697
• 46 Jiang Z, You L, Dou W. et al. Effects of an electric field on the conformational transition of the protein: a molecular dynamics simulation study. Polymers (Basel) 2019; 11: 282
• 47 Leeson PD. Molecular inflation, attrition and the rule of five. Adv Drug Deliv Rev 2016; 101: 22-33
• 48 Alex A, Millan DS, Perez M. et al. Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space. Medchemcomm 2011; 2: 669-674
• 49 Veber DF, Johnson SR, Cheng HY. et al. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 2002; 45: 2615-2623
• 50 Palm K, Stenberg P, Luthman K. et al. Polar molecular surface properties predict the intestinal absorption of drugs in humans. Pharmaceutical Research 1997; 14: 568-571
• 51 Lagorce D, Douguet D, Miteva MA. et al. Computational analysis of calculated physicochemical and ADMET properties of protein-protein interaction inhibitors. scientific reports 2017; 7: 1-15
• 52 Lipinski CA, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 1997; 23: 3-25
• 53 Mu JX, Shi YX, Yang MY. et al. Synthesis, crystal structure, DFT study and antifungal activity of 4-(5-((4-bromobenzyl)thio)-4-phenyl-4H-1,2,4-triazol-3- yl)pyridine. Crystals 2015; 6: 4
• 54 Fukui K, Yonezawa T, Shingu HA. Molecular orbital theory of reactivity in aromatic hydrocarbons. J Chem Phys 2004; 20: 722
• 55 Bartyzel A, Kaczor AA, Mahmoudi G. et al. Theoretical investigations on the HOMO–LUMO gap and global reactivity descriptor studies, natural bond orbital, and nucleus-independent chemical shifts analyses of 3-phenylbenzo[d]thiazole-2(3H)-imine and its parasubstituted derivatives: solvent and substituent effects. J Chem Res 2021; 45: 147-158