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Research Papers

Novel pyrrolopyrimidine derivatives: design, synthesis, molecular docking, molecular simulations and biological evaluations as antioxidant and anti-inflammatory agents

, , , , , , & show all
Pages 1821-1837 | Received 10 Mar 2022, Accepted 10 Jun 2022, Published online: 27 Jun 2022

References

  • Yu L, Feng Z. The role of toll-like receptor signaling in the progression of heart failure. Mediators Inflamm 2018;2018:9874109.
  • Zhang Y, Liang C. Innate recognition of microbial-derived signals in immunity and inflammation. Sci China Life Sci 2016;59:1210–7.
  • Wong SW, Kwon MJ, Choi AMK, et al. Fatty acids modulate toll-like receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts in a reactive oxygen species-dependent manner. J Biol Chem 2009;284:27384–92.
  • Wang Y, Song E, Bai B, Vanhoutte PM. Toll-like receptors mediating vascular malfunction: lessons from receptor subtypes. Pharmacol Ther 2016;158:91–100.
  • Momtazmanesh S, Perry G, Rezaei N. Toll-like receptors in Alzheimer’s disease. J Neuroimmunol 2020;348:577362.
  • Jialal I, Kaur H, Devaraj S. Toll-like receptor status in obesity and metabolic syndrome: a translational perspective. J Clin Endocrinol Metab 2014;99:39–48.
  • Farrugia M, Baron B. The role of toll-like receptors in autoimmune diseases through failure of the self-recognition mechanism. Int J Inflam 2017;2017:8391230.
  • Azam S, Jakaria M, Kim IS, et al. Regulation of toll-like receptor (TLR) signaling pathway by polyphenols in the treatment of age-linked neurodegenerative diseases: focus on TLR4 signaling. Front Immunol 2019;10:1000.
  • Huang Q-Q, Pope RM. The role of toll-like receptors in rheumatoid arthritis. Curr Rheumatol Rep 2009;11:357–64.
  • So EY, Ouchi T. The application of toll like receptors for cancer therapy. Int J Biol Sci 2010;6:675–81.
  • Tsujimoto H, Ono S, Efron PA, et al. Role of toll-like receptors in the development of sepsis. Shock 2008;29:315–21.
  • Li Y, Deng S-L, Lian Z-X, Yu K. Roles of toll-like receptors in nitroxidative stress in mammals. Cells 2019;8:576.
  • Yang L, Xie X, Tu Z, et al. The signal pathways and treatment of cytokine storm in COVID-19. Signal Transduct Target Ther 2021;6:1–20.
  • Masih A, Agnihotri AK, Srivastava JK, et al. Discovery of novel pyrazole derivatives as a potent anti-inflammatory agent in RAW264.7 cells via inhibition of NF-ĸB for possible benefit against SARS-CoV-2. J Biochem Mol Toxicol 2021;35:1–9.
  • Kim JS, Lee JY, Yang JW, et al. Immunopathogenesis and treatment of cytokine storm in COVID-19. Theranostics 2021;11:316–29.
  • Berríos-Cárcamo P, Quezada M, Quintanilla ME, et al. Oxidative stress and neuroinflammation as a pivot in drug abuse. A focus on the therapeutic potential of antioxidant and anti-inflammatory agents and biomolecules. Antioxidants 2020;9:830–26.
  • Gay NJ, Symmons MF, Gangloff M, Bryant CE. Assembly and localization of toll-like receptor signalling complexes. Nat Rev Immunol 2014;14:546–58.
  • Sellge G, Kufer TA. PRR-signaling pathways: learning from microbial tactics. Semin Immunol 2015;27:75–84.
  • Mukherjee S, Karmakar S, Babu SPS. TLR2 and TLR4 mediated host immune responses in major infectious diseases: a review. Brazilian J Infect Dis 2016;20:193–204.
  • Pudney J, X H, Z M, et al. Differential expression of toll-like receptors in the human placenta across early gestation. Placenta 2016;46:1–10.
  • Delneste Y, Beauvillain C, Jeannin P. Innate immunity: structure and function of TLRs. Medecine/Sciences 2007;23:67–73.
  • El-Zayat SR, Sibaii H, Mannaa FA. Toll-like receptors activation, signaling, and targeting: an overview. Bull Natl Res Cent 2019;43:187.
  • Medzhitov R, Preston-Hurlburt P, Janeway CA. A human homologue of the Drosophila toll protein signals activation of adaptive immunity. Nature 1997;388:394–7.
  • Lee CC, Avalos AM, Ploegh HL. Accessory molecules for Toll-like receptors and their function. Nat Rev Immunol 2012;12:168–79.
  • Molinaro A, Holst O, Lorenzo FD, et al. Chemistry of lipid A: at the heart of innate immunity. Chem - A Eur J 2015;21:500–19.
  • O'Neill LAJ, Golenbock D, Bowie AG. The history of Toll-like receptors-redefining innate immunity. Nat Rev Immunol 2013;13:453–60.
  • Park S, Shin H-J, Shah M, et al. TLR4/MD2 specific peptides stalled in vivo LPS-induced immune exacerbation. Biomaterials 2017;126:49–60.
  • Firmal P, Shah VK, Chattopadhyay S. Insight into TLR4-mediated immunomodulation in normal pregnancy and related disorders. Front Immunol 2020;11:807–16.
  • Ciesielska A, Matyjek M, Kwiatkowska K. TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling. Cell Mol Life Sci 2021;78:1233–61.
  • Yong-Bing X, Gui-Lin C, Ming-Quan G. Antioxidant and anti-inflammatory activities of the crude extracts of Moringa oleifera from Kenya and their correlations with flavonoids. Antioxidants 2019;8:296.
  • Battilocchio C, Poce G, Alfonso S, et al. A class of pyrrole derivatives endowed with analgesic/anti-inflammatory activity. Bioorganic Med Chem 2013;21:3695–701.
  • Kuzmich NN, Sivak KV, Chubarev VN, et al. TLR4 signaling pathway modulators as potential therapeutics in inflammation and sepsis. Vaccines 2017;5:34–25.
  • Mohame MS, Mostafa AG, El-hameed RHA, et al. Evaluation of the anti-inflammatory activity of novel synthesized pyrrole, pyrrolopyrimidine and spiropyrrolopyrimidine derivatives. Pharmacophore 2012;3:44–54.
  • Mohamed MS, Kamel R, Fatahala SS. Synthesis and biological evaluation of some thio containing pyrrolo [2, 3-d] pyrimidine derivatives for their anti-inflammatory and anti-microbial activities. Eur J Med Chem 2010;45:2994–3004.
  • Mohamed MS, Kamel R, Fathallah SS. Synthesis of new pyrroles of potential anti-inflammatory activity. Arch Pharm 2011;344:830–9.
  • Mohamed MS, Awad SM, Sayed AI. Synthesis of certain pyrimidine derivatives as antimicrobial agents and anti-inflammatory agents. Molecules 2010;15:1882–90.
  • Mohamed MS, Abd-El Hameed RH, Sayed AI, Soror SH. Novel antiviral compounds against gastroenteric viral infections. Arch Pharm 2015;348:194–205.
  • Mohamed MS, Sayed AI, Khedr MA, et al. Evaluation of novel pyrrolopyrimidine derivatives as antiviral against gastroenteric viral infections. Eur J Pharm Sci 2019;127:102–14.
  • Zander U, Hoffmann G, Cornaciu I, et al. Automated harvesting and processing of protein crystals through laser photoablation research papers. Acta Cryst 2016;72:454–66.
  • Jin MS, Kim SE, Heo JY, et al. Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell 2007;130:1071–82.
  • Friedman JM, Lee GH, Proenca R, et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996;379:632–5.
  • Kim HM, Park BS, Kim JI, et al. Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist eritoran. Cell 2007;130:906–17.
  • Abraham MJ, Murtola T, Schulz R, et al. Gromacs: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 2015;1-2:19–25.
  • Schüttelkopf AW, Van Aalten DMF. PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr Sect D Biol Crystallogr 2004;60:1355–63.
  • El Hassab MA, Eldehna WM, Al-Rashood ST, et al. Multi-stage structure-based virtual screening approach towards identification of potential SARS-CoV-2 NSP13 helicase inhibitors. J Enzyme Inhib Med Chem 2022;37:563–72.
  • Kumari R, Kumar R, Lynn A. g_mmpbsa—a GROMACS tool for high-throughput MM-PBSA calculations. J Chem Inf Model 2014;54:1951–62.
  • BLOIS MS. Antioxidant determinations by the use of a stable free radical. Nature 1958;181:1199–200.
  • Solaiman MA, Ali MA, Abdel-Moein NM, Mahmoud EA. Synthesis of Ag-NPs developed by green-chemically method and evaluation of antioxidant activities and anti-inflammatory of synthesized nanoparticles against LPS-induced NO in RAW 264.7 macrophages. Biocatal Agric Biotechnol 2020;29:101832.
  • Khor KZ, Joseph J, Shamsuddin F, et al. The cytotoxic effects of Moringa oleifera leaf extract and silver nanoparticles on human kasumi-1 cells. Int J Nanomedicine 2020;15:5661–70.
  • Vishwakarma A, Wany A, Pandey S, et al. Current approaches to measure nitric oxide in plants. J Exp Bot 2019;70:4333–43.
  • Zaki RM, El Dean AMK, El Monem MIA, Seddik MA. Novel synthesis and reactions of pyrazolyl-substituted tetrahydrothieno[2,3-c]isoquinoline derivatives. Heterocycl Commun 2016;22:103–9.
  • Hossain MI, Bhuiyan MMH. Synthesis and antimicrobial activities of some new thieno and furopyrimidine derivatives. J Sci Res 2009;1:317–25.
  • Flefel EM, El-Sofany WI, El-Shahat M, et al. Synthesis, molecular docking and in vitro screening of some newly synthesized triazolopyridine, pyridotriazine and pyridine-pyrazole hybrid derivatives. Molecules 2018;23:2548.
  • Mohamed MS, Kamel R, Abd El-Hameed RH. Evaluation of the anti-inflammatory activity of some pyrrolo[2,3-d] pyrimidine derivatives. Med Chem Res 2013;22:2244–52.
  • Fatahala SS, Khedr MA, Mohamed MS. Synthesis and structure activity relationship of some indole derivatives as potential anti-inflammatory agents. Acta Chim Slov 2017;64:865–76.
  • Fatahala SSSS, Hasabelnaby S, Goudah A, et al. Pyrrole and fused pyrrole compounds with bioactivity against inflammatory mediators. Molecules 2017;22:461–18.
  • Ghoshal T, Patel TM. Anticancer activity of benzoxazole derivative (2015 onwards): a review. Futur J Pharm Sci 2020;6:94.
  • Abdel-Mohsen SA. Synthesis, reactions and antimicrobial activity of 2-amino-4-(8-quinolinol-5-yl)-1-(p-tolyl)-pyrrole-3-carbonitrile. Bull Korean Chem Soc 2005;26:719–28.
  • Yehye WA, Abdul N, Arif A, et al. Understanding the chemistry behind the antioxidant activities of butylated hydroxytoluene (BHT): a review. Eur J Med Chem 2015;101:295–310.
  • Hsu FL, Huang WJ, Wu TH, et al. Evaluation of antioxidant and free radical scavenging capacities of polyphenolics from pods of Caesalpinia pulcherrima. Int J Mol Sci 2012;13:6073–88.
  • Debnath U, Mukherjee S, Joardar N, et al. Aryl quinolinyl hydrazone derivatives as anti-inflammatory agents that inhibit TLR4 activation in the macrophages. Eur J Pharm Sci 2019;134:102–15.
  • Almasaudi SB, El-Shitany NA, Abbas AT, et al. Antioxidant, anti-inflammatory, and antiulcer potential of manuka honey against gastric ulcer in rats. Oxid Med Cell Longev 2016;2016:3643824–10.
  • Klementiev B, Li S, Korshunova I, et al. Anti-inflammatory properties of a novel peptide interleukin 1 receptor antagonist. J Neuroinflammation 2014;11:27.
  • ElBordiny HS, El-Miligy MM, Kassab SE, et al. Design, synthesis, biological evaluation and docking studies of new 3-(4,5-dihydro-1H-pyrazol/isoxazol-5-yl)-2-phenyl-1H-indole derivatives as potent antioxidants and 15-lipoxygenase inhibitors. Eur J Med Chem 2018;145:594–605.
  • Amorim JL, Simas DLR, Pinheiro MMG, et al. Anti-inflammatory properties and chemical characterization of the essential oils of four Citrus species. PLoS One 2016;11:e0153643–18.
  • Toledo TR, Dejani NN, Monnazzi LGS, et al. Potent anti-inflammatory activity of pyrenocine A isolated from the marine-derived fungus Penicillium paxilli Ma(G)K. Mediators Inflamm 2014;2014:767061.
  • Jose SP, M R, S S, et al. Anti-inflammatory effect of Kaba Sura Kudineer (AYUSH approved COVID-19 drug)-a Siddha poly-herbal formulation against lipopolysaccharide induced inflammatory response in RAW-264.7 macrophages cells. J Ethnopharmacol 2022;283:114738.
  • Forcados GE, Muhammad A, Oladipo OO, et al. Metabolic implications of oxidative stress and inflammatory process in SARS-CoV-2 pathogenesis: therapeutic potential of natural antioxidants. Front Cell Infect Microbiol 2021;11:654813–1.
  • Saeedi-Boroujeni A, Mahmoudian-Sani MR. Anti-inflammatory potential of quercetin in COVID-19 treatment. J Inflamm 2021;18:1–9.
  • Rashid H. u, Martines MAU, Duarte AP, et al. Research developments in the syntheses, anti-inflammatory activities and structure-activity relationships of pyrimidines. RSC Adv 2021;11:6060–98.
  • Saleh HA, Yousef MH, Abdelnaser A. The anti-inflammatory properties of phytochemicals and their effects on epigenetic mechanisms involved in TLR4/NF-κB-mediated inflammation. Front Immunol 2021;12:606069–29.
  • Menche D. Design and synthesis of simplified polyketide analogs: new modalities beyond the rule of 5. ChemMedChem 2021;16:2068–74.
  • Wu J, Liu B, Mao W, et al. Prostaglandin E2 regulates activation of mouse peritoneal macrophages by Staphylococcus aureus through toll-like receptor 2, toll-like receptor 4, and NLRP3 inflammasome signaling. J Innate Immun 2020;12:154–69.
  • Ren H, Chen X, Jiang F, Li G. Cyclooxygenase-2 inhibition reduces autophagy of macrophages enhancing extraintestinal pathogenic Escherichia coli infection. Front Microbiol 2020;11:708–10.
  • Ono Y, Maejima Y, Saito M, et al. TAK-242, a specific inhibitor of Toll-like receptor 4 signalling, prevents endotoxemia-induced skeletal muscle wasting in mice. Sci Rep 2020;10:1–13.
  • Abdulkareem Aljumaily SA, Demir M, Elbe H, et al. Antioxidant, anti-inflammatory, and anti-apoptotic effects of crocin against doxorubicin-induced myocardial toxicity in rats. Environ Sci Pollut Res 2021;28:65802–13.
  • Makbal R, Idrissi FEJ, Ouchbani T, et al. Anti-inflammatory, antioxidant, chemical characterization, and safety assessment of Argania spinosa fruit shell extract from South-Western Morocco. Biomed Res Int 2021;2021:5536030.
  • Chen CJ, Liu YP. Mertk inhibition: potential as a treatment strategy in EGFR tyrosine kinase inhibitor-resistant non-small cell lung cancer. Pharmaceuticals 2021;14:130–25.
  • Ha MW, Paek SM. Recent advances in the synthesis of ibuprofen and naproxen. Molecules 2021;26:4792.
  • Santos-Sierra S. Targeting Toll-like receptor (TLR) pathways in inflammatory arthritis: two better than one? Biomolecules 2021;11:1291.
  • Chen L, Ji X, Wang M, et al. Involvement of TLR4 signaling regulated-COX2/PGE2 axis in liver fibrosis induced by Schistosoma japonicum infection. Parasites Vectors 2021;14:1–13.
  • Algehani RA, Abou R, Hegazy GA, et al. Colossolactone-G synergizes the anticancer properties of 5-fluorouracil and gemcitabine against colorectal cancer cells. Biomed Pharmacother 2021;140:111730.
  • ul Ain Q, Batool M, Choi S. TLR4-targeting therapeutics: structural basis and computer-aided drug discovery approaches. Molecules 2020;25:627.
  • Di Lorenzo A, Bolli E, Tarone L, et al. Toll-like receptor 2 at the crossroad between cancer cells, the immune system, and the microbiota. Int J Mol Sci 2020;21:9418–26.
  • Alizadeh M, Jalal M, Hamed K, et al. Recent updates on anti-inflammatory and antimicrobial effects of furan natural derivatives. J Inflamm Res 2020;13:451–63.
  • Cao H, Sethumadhavan K. Regulation of cell viability and anti-inflammatory tristetraprolin family gene expression in mouse macrophages by cottonseed extracts. Sci Rep 2020;10:1–11.
  • Wang Y, Zhang S, Li H, et al. Small-molecule modulators of Toll-like receptors. Acc Chem Res 2020;53:1046–55.
  • Nie X, Kitaoka S, Shinohara M, et al. Roles of Toll-like receptor 2/4, monoacylglycerol lipase, and cyclooxygenase in social defeat stress-induced prostaglandin E2 synthesis in the brain and their behavioral relevance. Sci Rep 2019;9:1–10.
  • Facchini FA, Zaffaroni L, Minotti A, et al. Structure-activity relationship in monosaccharide-based toll-like receptor 4 (TLR4) antagonists. J Med Chem 2018;61:2895–909.
  • Zaffaroni L, Peri F. Recent advances on Toll-like receptor 4 modulation: new therapeutic perspectives. Future Med Chem 2018;10:461–76.
  • Wang W, Wang J. Toll-like receptor 4 (TLR4)/cyclooxygenase-2 (COX-2) regulates prostate cancer cell proliferation, migration, and invasion by NF-κB activation. Med Sci Monit 2018;24:5588–97.
  • Wang X, Yao B, Wang Y, et al. Macrophage cyclooxygenase-2 protects against development of diabetic nephropathy. Diabetes 2017;66:494–504.
  • Lin A, Wang G, Zhao H, et al. TLR4 signaling promotes a COX-2/PGE2/STAT3 positive feedback loop in hepatocellular carcinoma (HCC) cells. Oncoimmunology 2016;5:e1074376–11.
  • Marshall JD, Heeke DS, Rao E, et al. A novel class of small molecule agonists with preference for human over mouse TLR4 activation. PLoS One 2016;11:e0164632–30.
  • Elisha IL, Dzoyem JP, McGaw LJ, et al. The anti-arthritic, anti-inflammatory, antioxidant activity and relationships with total phenolics and total flavonoids of nine South African plants used traditionally to treat arthritis. BMC Complement Altern Med 2016;16:1–10.
  • Makene VW, Pool EJ. The assessment of inflammatory activity and toxicity of treated sewage using RAW264.7 cells. Water Environ J 2015;29:353–9.
  • Chen CY, Kao CL, Liu CM. The cancer prevention, anti-inflammatory and anti-oxidation of bioactive phytochemicals targeting the TLR4 signaling pathway. Int J Mol Sci 2018;19:2729.
  • Zhao Y, Yang Y, Liu M, et al. COX-2 is required to mediate crosstalk of ROS- dependent activation of MAPK/NF-κ B signaling with pro-inflammatory response and defense-related NO enhancement during challenge of macrophage-like cell line with Giardia duodenalis. PLoS Negl Trop Dis 2022;16:e0010402.
  • Jannus F, Medina‐o’donnell M, Neubrand VE, et al. Efficient in vitro and in vivo anti‐inflammatory activity of a diamine‐pegylated oleanolic acid derivative. Int J Mol Sci 2021;22:8158.
  • Abd El-Hameed RH, Mahgoub S, El-Shanbaky HM, Mohamed MS, et al. Utility of novel 2-furanones in synthesis of other heterocyclic compounds having anti-inflammatory activity with dual COX2/LOX inhibition. J Enzyme Inhib Med Chem 2021;36:977–86.
  • Shen C, Liu H, Wang X, et al. Importance of incorporating protein flexibility in molecule modeling: a theoretical study on type I1/2 NIK inhibitors. Front Pharmacol 2019;10:345.
  • Hwang JH, Ma JN, Park JH, et al. Anti-inflammatory and antioxidant effects of MOK, a polyherbal extract, on lipopolysaccharide-stimulated RAW 264.7 macrophages. Int J Mol Med 2019;43:26–36.
  • Chen L, Zhang JP, Liu X, et al. Semisynthesis, an anti-inflammatory effect of derivatives of 1β-hydroxy alantolactone from Inula britannica. Molecules 2017;22:1835–8.
  • Lv H, Liu Q, Wen Z, et al. Xanthohumol ameliorates lipopolysaccharide (LPS)-induced acute lung injury via induction of AMPK/GSK3β-Nrf2 signal axis. Redox Biol 2017;12:311–24.
  • Banerjee AG, Das N, Shengule SA, et al. Synthesis, characterization, evaluation and molecular dynamics studies of 5, 6-diphenyl-1,2,4-triazin-3(2 H)-one derivatives bearing 5-substituted 1,3,4-oxadiazole as potential anti-inflammatory and analgesic agents. Eur J Med Chem 2015;101:81–95.
  • Bergandi L, Apprato G, Silvagno F. Antioxidant and anti-inflammatory activity of combined phycocyanin and palmitoylethanolamide in human lung and prostate epithelial cells. Antioxidants 2022;11:201.
  • Vien LT, Hanh TTH, Huong PTT, et al. Pyrrole oligoglycosides from the starfish Acanthaster planci suppress lipopolysaccharide-induced nitric oxide production in RAW264.7 macrophages. Chem Pharm Bull 2016;64:1654–7.
  • Mateev E, Georgieva M, Zlatkov A. Pyrrole as an important scaffold of anticancer drugs: recent advances. J Pharm Pharm Sci 2022;25:24–40.
  • Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: a current perspective. Biochem Pharmacol 2020;180:114147.
  • Jeelan Basha N, Basavarajaiah SM, Shyamsunder K. Therapeutic potential of pyrrole and pyrrolidine analogs: an update. Mol Divers 2022:1–23.
  • Lattuca B, Khoueiry Z, Malclès G, et al. Drug interactions between non-steroidal anti-inflammatory drugs and cardiovascular treatments (except anti-agregant therapy). Antiinflamm Antiallergy Agents Med Chem 2013;12:36–46.
  • Ushiyama S, Yamada T, Murakami Y, et al. Preclinical pharmacology profile of CS-706, a novel cyclooxygenase-2 selective inhibitor, with potent antinociceptive and anti-inflammatory effects. Eur J Pharmacol 2008;578:76–86.
  • Howes LG. Selective COX-2 inhibitors, NSAIDs and cardiovascular events – is celecoxib the safest choice? Ther Clin Risk Manag 2007;3:831–45.
  • Bocheva A, Bijev A, Nankov A. Further evaluation of a series of anti-inflammatory N-pyrrolylcarboxylic acids: effects on the nociception in rats. Arch Pharm 2006;339:141–4.
  • Lessigiarska I, Nankov A, Bocheva A, et al. 3D-QSAR and preliminary evaluation of anti-inflammatory activity of series of N-pyrrolylcarboxylic acids. Farmaco 2005;60:209–18.