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Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Synthesis of 1H-1,2,3-Triazole-Linked Quinoline-Isatin Molecular Hybrids as Anti-Breast Cancer and Anti-Methicillin-Resistant Staphylococcus aureus (MRSA) Agents

Author(s): Paul Awolade, Nosipho Cele, Oluwakemi Ebenezer, Nagaraju Kerru, Lalitha Gummidi, Liang Gu, Gabriella Palma, Mandeep Kaur and Parvesh Singh*

Volume 21, Issue 10, 2021

Published on: 29 September, 2020

Page: [1228 - 1239] Pages: 12

DOI: 10.2174/1871520620666200929153138

Price: $65


Background: The persistence of breast cancer as the leading cause of mortality among women, coupled with drug resistance to tamoxifen, the standard endocrine therapy for the disease, exacts continuous attention. To this effect, molecular hybridisation offers an attractive route to drugs with improved bioactivity profiles.

Objective: The primary goal of this study was to examine the potential of 1H-1,2,3-triazole linked quinolineisatin molecular hybrids as drug candidates against breast cancer and Methicillin-Resistant Staphylococcus aureus (MRSA) cells.

Methods: The quinoline-isatin hybrids were synthesised via click chemistry-mediated molecular hybridisation strategy. Anti-breast cancer activity was determined in 3-(4,5-dimethylthiazol-z-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using Estrogen-Responsive (ER+) MCF-7 and MDA-MB-231 (Triple-Negative Breast Cancer -TNBC) cells, while antimicrobial efficacy was established via the broth dilution method. Also, the toxicity profile of potent compounds to non-cancerous cells was determined using human embryonic kidney cells (HEK293) and human Red Blood Cells (hRBCs). In silico techniques were employed to predict the druglike properties of potent compounds and understand their binding modes with Estrogen Receptor alpha (ERα).

Results: Compounds 7g-i exhibited the strongest cytotoxicity to MCF-7 cells with IC50 values of 23.54, 23.66, and 32.50μM, respectively. Interestingly, compound 7h also emerged as the best drug candidate against MDAMB- 231 and MRSA cells with IC50=71.40μM and MIC80=27.34μM, respectively. Structure-activity relationship analysis revealed that quinoline-2-carbaldehyde and 5,7-disubstituted isatin moieties confer desirable potency. These compounds showed no significant cytotoxic or haemolytic effects on HEK293 or hRBCs in vitro at their active concentrations; hence, eliciting their selectivity for cancer cells. In silico studies also presented the drugability of potent compounds and the likely structural features interacting with amino acid residues at the ligandbinding domain of ERα.

Conclusion: These results suggest that the identified 1H-1,2,3-triazole-linked quinoline-isatin hybrids are viable chemotypes that can be adopted as templates for the development of new anti-breast cancer and anti-MRSA agents.

Keywords: Breast cancer, molecular hybridisation, isatin, quinoline, methicillin-resistant Staphylococcus aureus, in silico.

Graphical Abstract
World Health Organization Cancer..
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[] [PMID: 30207593]
Tsang, J.Y.S.; Tse, G.M. Molecular classification of breast cancer. Adv. Anat. Pathol., 2020, 27(1), 27-35.
[] [PMID: 31045583]
Dahlman-Wright, K.; Cavailles, V.; Fuqua, S.A.; Jordan, V.C.; Katzenellenbogen, J.A.; Korach, K.S.; Maggi, A.; Muramatsu, M.; Parker, M.G.; Gustafsson, J-Å. International Union of Pharmacology. LXIV. Estrogen receptors. Pharmacol. Rev., 2006, 58(4), 773-781.
[] [PMID: 17132854]
Paterni, I.; Granchi, C.; Katzenellenbogen, J.A.; Minutolo, F. Estrogen receptors alpha (ERα) and beta (ERβ): Subtype-selective ligands and clinical potential. Steroids, 2014, 90, 13-29.
[] [PMID: 24971815]
Warner, M.; Huang, B.; Gustafsson, J-A. Estrogen receptor β as a pharmaceutical target. Trends Pharmacol. Sci., 2017, 38(1), 92-99.
[] [PMID: 27979317]
Mukhopadhyay, U.K.; Oturkar, C.C.; Adams, C.; Wickramasekera, N.; Bansal, S.; Medisetty, R.; Miller, A.; Swetzig, W.M.; Silwal-Pandit, L.; Børresen-Dale, A-L.; Creighton, C.J.; Park, J.H.; Konduri, S.D.; Mukhopadhyay, A.; Caradori, A.; Omilian, A.; Bshara, W.; Kaipparettu, B.A.; Das, G.M. TP53 status as a determinant of pro- vs anti-tumorigenic effects of estrogen receptor-beta in breast cancer. J. Natl. Cancer Inst., 2019, 111(11), 1202-1215.
[] [PMID: 30990221]
Patel, H.K.; Bihani, T. Selective Estrogen Receptor Modulators (SERMs) and Selective Estrogen Receptor Degraders (SERDs) in cancer treatment. Pharmacol. Ther., 2018, 186, 1-24.
[] [PMID: 29289555]
Osborne, C.K.; Schiff, R. Mechanisms of endocrine resistance in breast cancer. Annu. Rev. Med., 2011, 62(1), 233-247.
[] [PMID: 20887199]
Ali, S.; Rasool, M.; Chaoudhry, H.; N, Pushparaj P.; Jha, P.; Hafiz, A.; Mahfooz, M.; Abdus Sami, G.; Azhar Kamal, M.; Bashir, S.; Ali, A.; Sarwar Jamal, M. Molecular mechanisms and mode of tamoxifen resistance in breast cancer. Bioinformation, 2016, 12(3), 135-139.
[] [PMID: 28149048]
Yang, G.; Nowsheen, S.; Aziz, K.; Georgakilas, A.G. Toxicity and adverse effects of Tamoxifen and other anti-estrogen drugs. Pharmacol. Ther., 2013, 139(3), 392-404.
[] [PMID: 23711794]
Rossolini, G.M.; Arena, F.; Pecile, P.; Pollini, S. Update on the antibiotic resistance crisis. Curr. Opin. Pharmacol., 2014, 18, 56-60.
[] [PMID: 25254623]
Peleg, A.Y.; Hooper, D.C. Hospital-acquired infections due to gram-negative bacteria. N. Engl. J. Med., 2010, 362(19), 1804-1813.
[] [PMID: 20463340]
Köck, R.; Becker, K.; Cookson, B.; Gemert-Pijnen, J.E.V.; Harbarth, S.; Kluytmans, J.; Mielke, M.; Peters, G.; Skov, R.L.; Struelens, M.J.; Tacconelli, E.; Torné, A.N.; Witte, W.; Friedrich, A.W. Methicillin-Resistant Staphylococcus aureus (MRSA): Burden of disease and control challenges in Europe. Euro Surveill., 2010, 15(41), 19688.
Foster, T.J. Antibiotic resistance in Staphylococcus aureus. Current status and future prospects. FEMS Microbiol. Rev., 2017, 41(3), 430-449.
[] [PMID: 28419231]
Xu, Z.; Zhao, S.J.; Liu, Y. 1,2,3-Triazole-containing hybrids as potential anticancer agents: Current developments, action mechanisms and structure-activity relationships. Eur. J. Med. Chem., 2019, 183, 111700.
[] [PMID: 31546197]
Zhang, B. Comprehensive review on the anti-bacterial activity of 1,2,3-triazole hybrids. Eur. J. Med. Chem., 2019, 168, 357-372.
[] [PMID: 30826511]
Bonandi, E.; Christodoulou, M.S.; Fumagalli, G.; Perdicchia, D.; Rastelli, G.; Passarella, D. The 1,2,3-triazole ring as a bioisostere in medicinal chemistry. Drug Discov. Today, 2017, 22(10), 1572-1581.
[] [PMID: 28676407]
Awolade, P.; Cele, N.; Kerru, N.; Singh, P. Synthesis, antimicrobial evaluation, and in silico studies of quinoline-1H-1,2,3-triazole molecular hybrids. Mol. Divers., 2020, Ahead of Print..
[ ] [PMID: 32507981]
Rani, A.; Singh, G.I.; Kaur, R.; Palma, G.; Perumal, S.; Kaur, M.; Ebenezer, O.; Awolade, P.; Singh, P.; Kumar, V. Azide-alkyne cycloaddition en route to ferrocenyl-methoxy-methyl-isatin-conjugates: Synthesis, anti-breast cancer activities and molecular docking studies. J. Organomet. Chem., 2020, 907, 121072.
Sharma, B.; Singh, A.; Gu, L.; Saha, S.T.; Singh-Pillay, A.; Cele, N.; Singh, P.; Kaur, M.; Kumar, V. Diastereoselective approach to rationally design tetrahydro-β-carboline-isatin conjugates as potential SERMs against breast cancer. RSC Advances, 2019, 9(17), 9809-9819.
Krawczyk, M.; Pastuch-Gawolek, G.; Mrozek-Wilczkiewicz, A.; Kuczak, M.; Skonieczna, M.; Musiol, R. Synthesis of 8-hydroxyquinoline glycoconjugates and preliminary assay of their β1,4-GalT inhibitory and anti-cancer properties. Bioorg. Chem., 2019, 84, 326-338.
[] [PMID: 30530074]
Basak, A.; Abouelhassan, Y.; Kim, Y.S.; Norwood, V.M., IV; Jin, S.; Huigens, R.W., III Halogenated quinolines bearing polar functionality at the 2-position: Identification of new antibacterial agents with enhanced activity against Staphylococcus epidermidis. Eur. J. Med. Chem., 2018, 155, 705-713.
[] [PMID: 29936357]
Irfan, M.; Alam, S.; Manzoor, N.; Abid, M. Effect of quinoline based 1,2,3-triazole and its structural analogues on growth and virulence attributes of Candida albicans. PLoS One, 2017, 12(4), e0175710.
[] [PMID: 28430797]
Gao, F.; Ye, L.; Kong, F.; Huang, G.; Xiao, J. Design, synthesis and antibacterial activity evaluation of moxifloxacin-amide-1,2,3-triazole-isatin hybrids. Bioorg. Chem., 2019, 91, 103162.
[] [PMID: 31382058]
European Collection of Authenticated Cell Cultures (ECACC). Fundamental Techniques in Cell Culture: Laboratory Handbook, 4th ed; MERCK: Darmstadt, 2018.
Zhang, J.H.; Chung, T.D.Y.; Oldenburg, K.R. A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J. Biomol. Screen., 1999, 4(2), 67-73.
[] [PMID: 10838414]
Roos, K.; Wu, C.; Damm, W.; Reboul, M.; Stevenson, J.M.; Lu, C.; Dahlgren, M.K.; Mondal, S.; Chen, W.; Wang, L.; Abel, R.; Friesner, R.A.; Harder, E.D. OPLS3e: Extending force field coverage for drug-like small molecules. J. Chem. Theory Comput., 2019, 15(3), 1863-1874.
[] [PMID: 30768902]
LigPrep; Schrödinger, LLC: New York, 2019.
Epik. Schrödinger, LLC, New York, . 2019.
QikProp, version 6.0; Schrödinger, LLC: New York, 2019.
CambridgeSoft ChemDraw Ultra 12.0. CambridgeSoft,. 2010.
Protein Preparation Wizard. Epik, Schrödinger, LLC, New York, 2019; Impact, Schrödinger, LLC, New York, 2019; Prime, Schrödinger, LLC: New York, 2019.
Induced Fit Docking protocol. Glide, Schrödinger, LLC, New York,. 2019.
Prime MM-GBSA; Schrödinger, LLC, New York,. , 2019.
Chan, S.H.; Chui, C.H.; Chan, S.W.; Kok, S.H.; Chan, D.; Tsoi, M.Y.; Leung, P.H.; Lam, A.K.; Chan, A.S.; Lam, K.H.; Tang, J.C. Synthesis of 8-hydroxyquinoline derivatives as novel antitumor agents. ACS Med. Chem. Lett., 2012, 4(2), 170-174.
[] [PMID: 24900641]
da Silva, B.N.; Bastos, R.S.; Silva, B.V.; Pinto, A.C. Preparation of 5-nitroisatin and 5-chloroisatin from isonitrosoacetanilide. Quim. Nova, 2010, 33(10), 2279-2282.
Gasparič, J.; Vontor, T.; Lyčka, A.; Šnobl, D. Formation of acetals and cleavage of the five-membered ring in the bromination of isatin in alcohols. Collect. Czech. Chem. Commun., 1990, 55, 2963-2966.
da Silva, J.F.M.; Garden, S.J.; Pinto, A.C. The chemistry of isatins: A review from 1975 to 1999. J. Braz. Chem. Soc., 2001, 12(3), 273-324.
Wang, Z. Comprehensive Organic Name Reactions and Reagents; John Wiley & Sons, Inc.: West Sussex, UK, 2010.
Sharma, B.; Gu, L.; Pillay, R.P.; Cele, N.; Awolade, P.; Singh, P.; Kaur, M.; Kumar, V. Design, synthesis and anti-proliferative evaluation of 1H-1,2,3-triazole grafted tetrahydro-β-carboline-chalcone/ferrocenylchalcone conjugates in estrogen responsive and triple negative breast cancer cells. New J. Chem., 2020, 44, 11137-11147.
Kumar, S.; Gu, L.; Palma, G.; Kaur, M.; Singh-Pillay, A.; Singh, P.; Kumar, V. Design, synthesis, anti-proliferative evaluation and docking studies of 1H-1,2,3-triazole tethered ospemifene-isatin conjugates as selective estrogen receptor modulators. New J. Chem., 2018, 42(5), 3703-3713.
Kumar, S.; Palma, G.; Perumal, S.; Kaur, M.; Singh-Pillay, A.; Raj, R.; Singh, P.; Kumar, V. Triarylethylene-indolin-2,3-dione molecular conjugates: Design, synthesis, docking studies and anti-proliferation evaluation. RSC Advances, 2019, 9(72), 42409-42414.
Hughes, J.D.; Blagg, J.; Price, D.A.; Bailey, S.; Decrescenzo, G.A.; Devraj, R.V.; Ellsworth, E.; Fobian, Y.M.; Gibbs, M.E.; Gilles, R.W.; Greene, N.; Huang, E.; Krieger-Burke, T.; Loesel, J.; Wager, T.; Whiteley, L.; Zhang, Y. Physiochemical drug properties associated with in vivo toxicological outcomes. Bioorg. Med. Chem. Lett., 2008, 18(17), 4872-4875.
[] [PMID: 18691886]
Lee, S.; Barron, M.G. Structure-based understanding of binding affinity and mode of estrogen receptor α agonists and antagonists. PLoS One, 2017, 12(1), e0169607..
[] [PMID: 28061508]
Tsakovska, I.; Pajeva, I.; Alov, P.; Worth, A. Recent advances in the molecular modeling of estrogen receptor-mediated toxicity., Adv. Protein Chem. Struct. Biol., 2011, 85, 217-251..
Gleeson, M.P.; Leeson, P.D.; van de Waterbeemd, H. Physicochemical properties and compound quality. In: The Handbook of Medicinal Chemistry: Principles and Practice; 4th ed.; Davis, A.; Ward, S. E., Eds. The Royal Society of Chemistry, 2014, pp. 1-31.

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