NOVEL HYBRIDS OF QUINOLINE LINKED PYRIMIDINE DERIVATIVES AS CYCLOOXYGENASE INHIBITORS: MOLECULAR DOCKING, ADMET STUDY, AND MD SIMULATION
DOI:
https://doi.org/10.22159/ijap.2024v16i6.52023Keywords:
Quinoline, Pyrimidine, Cyclooxygenase, Molecular docking, Molecular dynamicsAbstract
Objective: Finding novel anti-inflammatory compounds is a crucial sector of research, despite the significant advances this field has made. Inefficiency and unfavorable side effects are indeed potential drawbacks of conventional therapy utilizing steroidal or nonsteroidal drugs. This study aims to screen the designed quinoline-linked pyrimidine derivatives as Cyclooxygenase (COX) inhibitors.
Methods: In the present study, we assessed the binding interactions of designed quinoline-linked pyrimidine derivatives with COX enzymes using a molecular docking approach. Using Molecular Dynamics (MD) simulations, the compound’s behavior was further investigated and its stability and conformational dynamics were demonstrated. Schrödinger's QikProp program was utilized to analyze the Absorption, Distribution, Metabolism, and Excretion (ADME) properties and toxicity properties were further investigated using Osiris Property Explorer. Additionally, the protein-ligand complexes' binding free energy has been ascertained using the Molecular Mechanics/ Generalized Born Surface Area (MM-GBSA) approach, which offered crucial information regarding the strength of their interactions.
Results: The designed quinoline-linked pyrimidine derivatives fulfilled the Lipinski Rule of Five and had physicochemical characteristics within acceptable ranges, better ADME properties, and were non-toxic. Among the designed compounds, QPDU1 and QPDT6 showed correspondingly good docking scores for COX-1 and COX-2. QPDT6 was additionally analyzed by MD simulation studies to thoroughly examine the interaction between protein and ligand and their stability.
Conclusion: The proposed compounds exhibit strong binding affinities to COX enzymes, stable interactions in MD simulations, and favorable drug-like features. These results support the need for more research and development of these substances as possible anti-inflammatory drugs
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References
Baranwal J, Kushwaha S, Singh S, Jyoti A. A review on the synthesis and pharmacological activity of heterocyclic compounds. Current Physical Chemistry. 2023;13(1):2-19. https://doi.org/10.2174/1877946813666221021144829
Yadav P, Shah K. Quinolines, a perpetual, multipurpose scaffold in medicinal chemistry. Bioorg Chem. 2021;109:104639. https://doi.org/10.1016/j.bioorg.2021.104639
Kaur R, Kumar K. Synthetic and medicinal perspective of quinolines as antiviral agents. Eur J Med Chem. 2021;215:113220. https://doi.org/10.1016/j.ejmech.2021.113220
Kharb R, Kaur H. Therapeutic significance of quinoline derivatives as antimicrobial agents. International research journal of pharmacy. 2013;4(3):63-9. https://doi.org/10.7897/2230-8407.04311
Singh SK, Singh S. A brief history of quinoline as antimalarial agents. Int J Pharm Sci Rev Res. 2014;25(1):295-302.
Coa JC, Castrillón, LW, Cardona, GW, Carda M, Ospina V, Muñoz JA, Vélez ID, Robledo SM. Synthesis, leishmanicidal, trypanocidal and cytotoxic activity of quinoline hydrazone hybrids. Eur J Med Chem. 2015, EJMECH 7999. http://dx.doi.org/10.1016/j.ejmech.2015.07.018
Ilakiyalakshmi M, Napoleon AA. Review on recent development of quinoline for anticancer activities. Arab J Chem. 2022;15(11):104168. https://doi.org/10.1016/j.arabjc.2022.104168
Khalifa NM, Al-Omar MA, Abd El-Galil AA, Abd El-Reheem M. Anti-inflammatory and analgesic activities of some novel carboxamides derived from 2-phenyl quinoline candidates. Biomed Res. 2017;28(2):869-74.
Mahajan P, Nikam M, Asrondkar A, Bobade A, Gill C. Synthesis, antioxidant, and anti‐inflammatory evaluation of novel thiophene‐fused quinoline based β‐diketones and derivatives. J Heterocycl Chem. 2017;54(2):1415-22. https://doi.org/10.1002/jhet.2722
Mandewale MC, Patil UC, Shedge SV, Dappadwad UR, Yamgar RS. A review on quinoline hydrazone derivatives as a new class of potent antitubercular and anticancer agents. Beni-SuefUniv J Basic Appl Sci. 2017;6(4):354-61. https://doi.org/10.1016/j.bjbas.2017.07.005
Das P, Deng X, Zhang L, Roth MG, Fontoura BM, Phillips MA, De Brabander JK. SAR-based optimization of a 4-quinoline carboxylic acid analogue with potent antiviral activity. ACS Med Chem Lett. 2013;4(6):517-21. https://doi.org/10.1021/ml300464h
Dorababu A. Recent update on antibacterial and antifungal activity of quinoline scaffolds. Arch Pharm. 2021;354(3):2000232. https://doi.org/10.1002/ardp.202000232
Mouscadet JF, Desmaële D. Chemistry and structure-activity relationship of the styrylquinoline-type HIV integrase inhibitors. Molecules. 2010;15(5):3048-78. https://doi.org/10.3390/molecules15053048
Zajdel P, Marciniec K, Maślankiewicz A, Grychowska K, Satała G, Duszyńska B, Lenda T, Siwek A, Nowak G, Partyka A, Wróbel D. Antidepressant and antipsychotic activity of new quinoline-and isoquinoline-sulfonamide analogs of aripiprazole targeting serotonin 5-HT1A/5-HT2A/5-HT7 and dopamine D2/D3 receptors. Eur J of Med Chem. 2013;60:42-50. https://doi.org/10.1016/j.ejmech.2012.11.042
Wei CX, Deng XQ, Chai KY, Sun ZG, Quan ZS. Synthesis and anticonvulsant activity of 1-formamide-triazolo [4, 3-a] quinoline derivatives. Arch Pharm Res. 2010;33:655. https://doi.org/10.1007/s12272-010-0502-0
Kumar A, Kumar P, Shetty CR, James JP, Shetty HC. Synthesis, antidiabetic evaluation and bioisosteric modification of quinoline incorporated 2-pyrazoline derivatives. Indian J Pharm Educ Res. 2021;55(2):574-80. http://dx.doi.org/10.5530/ijper.55.2.96
Cai Z, Zhou W, Sun L. Synthesis and HMG CoA reductase inhibition of 4-thiophenyl quinolines as potential hypocholesterolemic agents. Bioorg Med Chem. 2007;15(24):7809-29. https://doi.org/10.1016/j.bmc.2007.08.044
Kumar Gupta S, Mishra A. Synthesis, characterization & screening for anti-inflammatory & analgesic activity of quinoline derivatives bearing azetidinones scaffolds. Anti-Inflamm Anti-Allergy Agents Med Chem. 2016;15(1):31-43. https://doi.org/10.2174/1871523015666160210124545
Wang XQ, Zhao CP, Zhong LC, Zhu DL, Mai DH, Liang MG, He MH. Preparation of 4-flexible amino-2-arylethenyl-quinoline derivatives as multi-target agents for the treatment of alzheimer’s disease. Molecules. 2018;23(12):3100. https://doi.org/10.3390/molecules23123100
Sashidhara KV, Avula SR, Mishra V, Palnati GR, Singh LR, Singh N, Chhonker YS, Swami P, Bhatta RS. Identification of quinoline-chalcone hybrids as potential antiulcer agents. Eur J Med Chem. 2015;89:638-53. https://doi.org/10.1016/j.ejmech.2014.10.068
Sharma V, Chitranshi N, Agarwal AK. Significance and biological importance of pyrimidine in the microbial world. International journal of medicinal chemistry. 2014;2014(1):202784. https://doi.org/10.1155/2014/202784
Kalčic F, Kolman V, Ajani H, Zídek Z, Janeba Z. Polysubstituted pyrimidines as mPGES‐1 Inhibitors: Discovery of potent inhibitors of PGE2 production with strong anti‐inflammatory effects in carrageenan‐induced rat paw edema. Chem Med Chem. 2020;15(15):1398-407. https://doi.org/10.1002/cmdc.202000258
Abd El-Aleam RH, George RF, Hassan GS, Abdel-Rahman HM. Synthesis of 1, 2, 4-triazolo [1, 5-a] pyrimidine derivatives: Antimicrobial activity, DNA gyrase inhibition and molecular docking. Bioorg Chem. 2020;94:103411. https://doi.org/10.1016/j.bioorg.2019.103411
Kumar B, Sharma P, Gupta VP, Khullar M, Singh S, Dogra N, Kumar V. Synthesis and biological evaluation of pyrimidine bridged combretastatin derivatives as potential anticancer agents and mechanistic studies. Bioorg Chem. 2018;78:130-40. https://doi.org/10.1016/j.bioorg.2018.02.027
Huang B, Kang D, Tian Y, Daelemans D, De Clercq E, Pannecouque C, Zhan P, Liu X. Design, synthesis, and biological evaluation of piperidinyl‐substituted [1, 2, 4] triazolo [1, 5‐a] pyrimidine derivatives as potential anti‐HIV‐1 agents with reduced cytotoxicity. Chem Biol Drug Des. 2021;97(1):67-76. https://doi.org/10.1111/cbdd.13760
Bruno O, Schenone S, Ranise A, Bondavalli F, Barocelli E, Ballabeni V, Chiavarini M, Bertoni S, Tognolini M, Impicciatore M. New polycyclic pyrimidine derivatives with antiplatelet in vitro activity: synthesis and pharmacological screening. Bioorg Med Chem. 2001;9(3):629-36. https://doi.org/10.1016/s0968-0896(00)00272-8
Farghaly AM, AboulWafa OM, Elshaier YA, Badawi WA, Haridy HH, Mubarak HA. Design, synthesis, and antihypertensive activity of new pyrimidine derivatives endowing new pharmacophores. Med Chem Res. 2019;28:360-79. https://doi.org/10.1007/S00044-019-02289-6
Farghaly TA, Harras MF, Alsaedi AM, Thakir HA, Mahmoud HK, Katowah DF. Antiviral activity of pyrimidine containing compounds: Patent review. Mini Rev Med Chem. 2023;23(7):821-51. https://doi.org/10.2174/1389557523666221220142911
Wu W, Lan W, Wu C, Fei Q. Synthesis and antifungal activity of pyrimidine derivatives containing an amide moiety. Front Chem. 2021;9:695628. https://doi.org/10.3389/fchem.2021.695628
Pant S, Kumar K R, Rana P, Anthwal T, Ali SM, Gupta M, Chauhan M, Nain S. Novel substituted pyrimidine derivatives as potential anti-alzheimer’s agents: Synthesis, biological, and molecular docking studies. ACS Chem Neurosci. 2024;15(4):783-97.https://doi.org/10.1021/acschemneuro.3c00662
Gupta A, Bhat HR, Singh UP. Discovery of novel hybrids of Morpholino-1, 3, 5-triazine-pyrimidine as an anti-diabetic agent in high-fat, low-dose streptozotocin-induced diabetes in wistar rats: An in vitro, in silico and in vivo study. J Mol Struct. 2023;1294:136478. https://doi.org/10.1016/j.molstruc.2023.136478
Liu P, Yang Y, Tang Y, Yang T, Sang Z, Liu Z, Zhang T, Luo Y. Design and synthesis of novel pyrimidine derivatives as potent antitubercular agents. Eur J Med Chem. 2019;163:169-82. https://doi.org/10.1016/j.ejmech.2018.11.054
Nair N, Majeed J, Pandey PK, Sweety R, Thakur R. Antioxidant potential of pyrimidine derivatives against oxidative stress. Indian J Pharm Sci. 2022;84(1):14-26. http://dx.doi.org/10.36468/pharmaceutical-sciences.890
Mathew B, Suresh J, Anbazhagan S. Development of novel (1-H) benzimidazole bearing pyrimidine-trione based MAO-A inhibitors: Synthesis, docking studies and antidepressant activity. J Saudi Chem Soc. 2016;20:S132-9. http://dx.doi.org/10.1016/j.jscs.2012.09.015
Arora N, Pandeya SN. Synthesis and analgesic activity of novel pyrimidine derivatives. Synthesis. 2011;11(1):48–52.
Mohana KN, Kumar BN, Mallesha L. Synthesis and biological activity of some pyrimidine derivatives. Drug Invent Today. 2013;5(3):216-22. http://dx.doi.org/10.1016/j.dit.2013.08.004
Kumar B, Kumar M, Dwivedi AR, Kumar V. Synthesis, biological evaluation and molecular modelling studies of propargyl‐containing 2, 4, 6‐trisubstituted pyrimidine derivatives as potential anti‐parkinson agents. Chem Med Chem. 2018;13(7):705-12. https://doi.org/10.1002/cmdc.201700589
Jain KS. A Novel 2, 4-dihalothieno [2, 3-d] pyrimidine as antihyperlipidemic agent: Synthesis, biological evaluation and investigation into its mechanism of action. EC Pharmacology and Toxicology. 2019;7:125-43.
Chandana L, Bhikshapathi DR. Ethnopharmacological investigation of Pleurotus ostreatus for anti-oxidative and anti-inflammatory activity in experimental animals. Asian Journal of Pharmaceutical and Clinical Research. 2024;17(4);37-41 https://doi.org/10.22159/ajpcr.2024.v17i4.49533
Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget. 2018;9(6):7204. https://doi.org/10.18632%2Foncotarget.23208
El-Sharief MA, Abbas SY, El-Sharief AM, Sabry NM, Moussa Z, El-Messery SM, Elsheakh AR, Hassan GS, El Sayed MT. 5-Thioxoimidazolidine-2-one derivatives: Synthesis, anti-inflammatory activity, analgesic activity, COX inhibition assay and molecular modelling study. Bioorg Chem. 2019;87:679-87. https://doi.org/10.1016/j.bioorg.2019.03.075
Dvorakova M, Langhansova L, Temml V, Pavicic A, Vanek T, Landa P. Synthesis, inhibitory activity, and in silico modeling of selective COX-1 inhibitors with a quinazoline core. ACS Med Chem Lett. 2021;12(4):610-6. https://doi.org/10.1021/acsmedchemlett.1c00004
Hawash M, Jaradat N, Hameedi S, Mousa A. Design, synthesis and biological evaluation of novel benzodioxole derivatives as COX inhibitors and cytotoxic agents. BMC Chem. 2020;14(1):1-9.https://doi.org/10.1186%2Fs13065-020-00706-1
Cardinal S, Paquet-Côté PA, Azelmat J, Bouchard C, Grenier D, Voyer N. Synthesis and anti-inflammatory activity of isoquebecol. Bioorg Med Chem. 2017;25(7):2043-56. https://doi.org/10.1016/j.bmc.2017.01.050
Dhawale S, Gawale S, Jadhav A, Gethe K, Raut P, Hiwarale N, Bhosale P, Tapadiya G. In silico approach targeting polyphenol as FabH inhibitor in bacterial infection. International Journal of Pharmacy and Pharmaceutical Sciences. 2022;14(11):25-30. https://doi.org/10.22159/ijpps.2022v14i11.45816
Jays J, Saravanan J. A molecular modelling approach for structure-based virtual screening and identification of novel isoxazoles as potential antimicrobial agents against S. Aureus. International Journal of Pharmacy and Pharmaceutical Sciences. 2024;16(4):36-41. https://dx.doi.org/10.22159/ijpps.2024v16i4.49731
Elmi A, Sayem SA, Ahmed M, Abdoul-Latif F. Natural compounds from djiboutian medicinal plants as inhibitors of covid-19 by in silico investigations. International Journal of Current Pharmaceutical Research.2020;12(4):52-7. https://doi.org/10.22159/ijcpr.2020v12i4.39051
Chand J, Kandy AT, Prasad K, Mathew J, Sherin F, Subramanian G. In silico, preparation and in vitro studies of benzylidene-based hydroxy benzyl urea derivatives as free radical scavengers in parkinson’s disease. Int J App Pharm. 2024;16(3):217-24.https://doi.org/10.22159/ijap.2024v16i3.50628
Sachdeo R, Khanwelkar C, Shete A. In silico exploration of berberine as a potential wound healing agent via network pharmacology, molecular docking, and molecular dynamics simulation. Int J App Pharm. 2024;16(2):188-94. https://doi.org/10.22159/ijap.2024v16i2.49922
Ismail NZ, Annamalai N, Zain NN, Arsad H. Molecular docking of selected compounds from Clinacanthus nutans with BCL-2, p53, caspase-3 and caspase-8 proteins in the apoptosis pathway. Journal of biological and scientific opinion. 2020;8(1):4-11. http://dx.doi.org/10.7897/2321-6328.081119
Baqi MA, Jayanthi K, R RK. Identification of benzylidene amino phenol inhibitors targeting thymidylate kinase for colon cancer treatment through in silico studies. Int J App Pharm. 2024;16(4):92–9. https://doi.org/10.22159/ijap.2024v16i4.50874
Mahantheshappa SS, Shivanna H, Satyanarayan ND. Synthesis, antimicrobial, antioxidant, and ADMET studies of quinoline derivatives. European Journal of Chemistry. 2021;12(1):37-44. https://doi.org/10.5155/eurjchem.12.1.37-44.2038
Mhaske GS, Thorat SR, Pawar VS, Pawar RS, Jambhulkar SR, Ghumre OA. Computational molecular docking and in silico, ADMET prediction studies of quinoline derivatives as EPHB4 inhibitor. Current Indian Science. 2024;2:1-16. http://dx.doi.org/10.2174/012210299X265033240116113623
El-Feky SA, Abd El-Samii ZK, Osman NA, Lashine J, Kamel MA, Thabet HK. Synthesis, molecular docking and anti-inflammatory screening of novel quinoline incorporated pyrazole derivatives using the Pfitzinger reaction II. Bioorg Chem. 2015;58:104-16. https://doi.org/10.1016/j.bioorg.2014.12.003
Abdelrahman MH, Youssif BG, Abdelazeem AH, Ibrahim HM, Abd El Ghany AM, Treamblu L, Bukhari SN. Synthesis, biological evaluation, docking study and ulcerogenicity profiling of some novel quinoline-2-carboxamides as dual COXs/LOX inhibitors endowed with anti-inflammatory activity. Eur J Med Chem. 2017;127:972-85. https://doi.org/10.1016/j.ejmech.2016.11.006
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