Current Computer-Aided Drug DesignCurrent Computer-Aided Drug DesignCurrent Computer-Aided Drug Design1573-40991875-6697Bentham Science64404210.2174/1573409919666230321145543ChemistryResearch ArticleSynthesis and in-silico Studies of 4-phenyl thiazol-2-amine Derivatives as Putative Anti-breast Cancer AgentsLavanyaKanamarlapudiinfo@benthamscience.netKaurKamalpreetinfo@benthamscience.netJaitakVikasinfo@benthamscience.netDepartment of Pharmaceutical Sciences and Natural Products, Central University of Punjab0104202420437438307012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://journals.eco-vector.com/1573-4099/article/view/644042

Background:Breast cancer (BC) is the second-leading cause of cancer-related fatalities in women after lung cancer worldwide. The development of BC is significantly influenced by estrogen receptors (ERs). The problem with current cancer treatments is selectivity, target specificity, cytotoxicity, and developing resistance. Thiazole scaffolds are gaining popularity in drug discovery due to their broad range of biological activity. It has the extraordinary capacity to control a variety of cellular pathways, and its potential for selective anticancer activity can be explored.

Objectives:Synthesis and in-silico studies of 4-Phenyl thiazol-2-amine derivatives as anti-breast cancer agents and molecular docking was used to assess the compounds’ capacity to bind ER-α protein target.

Methods:In this study, 4-Phenylthiazol-2-amine derivatives (3a-j) have been synthesized, and using Schrodinger software, molecular docking and ADME studies of the compounds were conducted.

Results:Most of the synthesized compounds have shown dock scores ranging from -6.658 to - 8.911 kcal/mol, which is better than the standard drug tamoxifen (-6.821 kcal/mol). According to molecular docking, all compounds fit in the protein’s active site and have the same hydrophobic pocket as the standard drug tamoxifen. Further, all of the compounds’ ADME properties are below acceptable limits.

Conclusion:Compound 3e showed the best docking score of -8.911. All compounds’ ADME properties are within acceptable limits, and their p/o coefficients fall within a range, suggesting they will all have sufficient absorption at the site of action. These compounds can be evaluated invitro and in-vivo in the future.

Thiazoleanti-cancerbreast cancerestrogen receptor alphamolecular dockingADME.Ayati, A.; Emami, S.; Moghimi, S.; Foroumadi, A. Thiazole in the targeted anticancer drug discovery. Future Med. Chem., 2019, 11(15), 1929-1952. doi: 10.4155/fmc-2018-0416 PMID: 31313595Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2022. CA Cancer J. Clin., 2022, 72(1), 7-33. doi: 10.3322/caac.21708 PMID: 35020204Uhlen, M.; Zhang, C.; Lee, S.; Sjöstedt, E.; Fagerberg, L.; Bidkhori, G.; Benfeitas, R.; Arif, M.; Liu, Z.; Edfors, F.; Sanli, K.; von Feilitzen, K.; Oksvold, P.; Lundberg, E.; Hober, S.; Nilsson, P.; Mattsson, J.; Schwenk, J.M.; Brunnström, H.; Glimelius, B.; Sjöblom, T.; Edqvist, P.H.; Djureinovic, D.; Micke, P.; Lindskog, C.; Mardinoglu, A.; Ponten, F. A pathology atlas of the human cancer transcriptome. Science, 2017, 357(6352), eaan2507. doi: 10.1126/science.aan2507 PMID: 28818916Dandriyal, R.; Pandit, N.; Rao, S.C.; Sapra, G.; Sharma, H.; Agarwal, U. Psammomatoid juvenile aggressive ossifying fibroma of mandible. Natl. J. Maxillofac. Surg., 2012, 3(1), 47-50. doi: 10.4103/0975-5950.102155 PMID: 23251058Li, C.I.; Uribe, D.J.; Daling, J.R. Clinical characteristics of different histologic types of breast cancer. Br. J. Cancer, 2005, 93(9), 1046-1052. doi: 10.1038/sj.bjc.6602787 PMID: 16175185Dossus, L.; Benusiglio, P.R. Lobular breast cancer: incidence and genetic and non-genetic risk factors. Breast Cancer Res., 2015, 17(1), 37. doi: 10.1186/s13058-015-0546-7 PMID: 25848941Blowman, K.; Magalhães, M.; Lemos, M.; Cabral, C.; Pires, I. Anticancer properties of essential oils and other natural products. Evid. Based Complement. Altern. Med., 2018, 2018.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. doi: 10.1016/j.pharmthera.2017.12.012 PMID: 29289555Martinkovich, S.; Shah, D.; Planey, S.L.; Arnott, J.A. Selective estrogen receptor modulators: tissue specificity and clinical utility. Clin. Interv. Aging, 2014, 9, 1437-1452. PMID: 25210448Foryst-Ludwig, A.; Kintscher, U. Metabolic impact of estrogen signalling through ERalpha and ERbeta. J. Steroid Biochem. Mol. Biol., 2010, 122(1-3), 74-81. doi: 10.1016/j.jsbmb.2010.06.012 PMID: 20599505Jia, M.; Dahlman-Wright, K.; Gustafsson, J.Å. Estrogen receptor alpha and beta in health and disease. Best Pract. Res. Clin. Endocrinol. Metab., 2015, 29(4), 557-568. doi: 10.1016/j.beem.2015.04.008 PMID: 26303083Anbalagan, M.; Rowan, B.G. Estrogen receptor alpha phosphorylation and its functional impact in human breast cancer. Mol. Cell. Endocrinol., 2015, 418(Pt 3), 264-272. doi: 10.1016/j.mce.2015.01.016 PMID: 25597633Lee, J.Y.; Kim, H.S.; Song, Y.S. Genistein as a potential anticancer agent against ovarian cancer. J. Tradit. Complement. Med., 2012, 2(2), 96-104. doi: 10.1016/S2225-4110(16)30082-7 PMID: 24716121Jordan, V.C.; Gapstur, S.; Morrow, M. Selective estrogen receptor modulation and reduction in risk of breast cancer, osteoporosis, and coronary heart disease. J. Natl. Cancer Inst., 2001, 93(19), 1449-1457. doi: 10.1093/jnci/93.19.1449 PMID: 11584060Riggs, B.L.; Hartmann, L.C. Selective estrogen-receptor modulators - mechanisms of action and application to clinical practice. N. Engl. J. Med., 2003, 348(7), 618-629. doi: 10.1056/NEJMra022219 PMID: 12584371Yavropoulou, M.P.; Makras, P.; Anastasilakis, A.D. Bazedoxifene for the treatment of osteoporosis. Expert Opin. Pharmacother., 2019, 20(10), 1201-1210. doi: 10.1080/14656566.2019.1615882 PMID: 31091133Singh, A.K.; Raj, V.; Saha, S. Indole-fused azepines and analogues as anticancer lead molecules: Privileged findings and future directions. Eur. J. Med. Chem., 2017, 142, 244-265. doi: 10.1016/j.ejmech.2017.07.042 PMID: 28803677Dandriyal, J.; Kaur, K.; Jaitak, V. Synthesis and in silico studies of c-4 substituted coumarin analogues as anticancer agents. Curr. Computeraided Drug Des., 2021, 17(4), 560-570. doi: 10.2174/1573409916666200628104638 PMID: 32598267Ayati, A.; Emami, S.; Asadipour, A.; Shafiee, A.; Foroumadi, A. Recent applications of 1,3-thiazole core structure in the identification of new lead compounds and drug discovery. Eur. J. Med. Chem., 2015, 97, 699-718. doi: 10.1016/j.ejmech.2015.04.015 PMID: 25934508Kashyap, S.J.; Garg, V.K.; Sharma, P.K.; Kumar, N.; Dudhe, R.; Gupta, J.K. Thiazoles: having diverse biological activities. Med. Chem. Res., 2012, 21(8), 2123-2132. doi: 10.1007/s00044-011-9685-2Rouf, A.; Tanyeli, C. Bioactive thiazole and benzothiazole derivatives. Eur. J. Med. Chem., 2015, 97, 911-927. doi: 10.1016/j.ejmech.2014.10.058 PMID: 25455640Mishra, R.; Sharma, P.K.; Verma, P.K.; Tomer, I.; Mathur, G.; Dhakad, P.K. Biological potential of thiazole derivatives of synthetic origin. J. Heterocycl. Chem., 2017, 54(4), 2103-2116. doi: 10.1002/jhet.2827Jaitak, V. Sahil; Kaur, K. Thiazole and related heterocyclic systems as anticancer agents: A review on synthetic strategies, mechanisms of action and SAR studies. Curr. Med. Chem., 2022, 29(29), 4958-5009. doi: 10.2174/0929867329666220318100019 PMID: 35306982Sharma, P.C.; Bansal, K.K.; Sharma, A.; Sharma, D.; Deep, A. Thiazole-containing compounds as therapeutic targets for cancer therapy. Eur. J. Med. Chem., 2020, 188, 112016. doi: 10.1016/j.ejmech.2019.112016 PMID: 31926469El-Mawgoud, H.K.A. Synthesis, in-vitro cytotoxicity and antimicrobial evaluations of some novel thiazole based heterocycles. Chem. Pharm. Bull., 2019, 67(12), 1314-1323. doi: 10.1248/cpb.c19-00681 PMID: 31787658Liu, X.H.; Lv, P.C.; Xue, J.Y.; Song, B.A.; Zhu, H.L. Novel 2,4,5-trisubstituted oxazole derivatives: Synthesis and antiproliferative activity. Eur. J. Med. Chem., 2009, 44(10), 3930-3935. doi: 10.1016/j.ejmech.2009.04.019 PMID: 19423198Sun, M.; Xu, Q.; Xu, J.; Wu, Y.; Wang, Y.; Zuo, D.; Guan, Q.; Bao, K.; Wang, J.; Wu, Y.; Zhang, W. Synthesis and bioevaluation of N,4-diaryl-1,3-thiazole-2-amines as tubulin inhibitors with potent antiproliferative activity. PLoS One, 2017, 12(3), e0174006. doi: 10.1371/journal.pone.0174006 PMID: 28333984Macaev, F. What can be done with the acetyl group of aryl-1 ethanones? Chem. J. Moldova, 2006, 1(1), 36-49. doi: 10.19261/cjm.2006.01(1).10Friggeri, L.; Hargrove, T.Y.; Wawrzak, Z.; Blobaum, A.L.; Rachakonda, G.; Lindsley, C.W.; Villalta, F.; Nes, W.D.; Botta, M.; Guengerich, F.P.; Lepesheva, G.I. Sterol 14α-Demethylase structure-based design of VNI ((R)- N -(1-(2,4-Dichlorophenyl)-2-(1 H -imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide)) derivatives to target fungal infections: Synthesis, biological evaluation, and crystallographic analysis. J. Med. Chem., 2018, 61(13), 5679-5691. doi: 10.1021/acs.jmedchem.8b00641 PMID: 29894182Roy, K.K.; Singh, S.; Sharma, S.K.; Srivastava, R.; Chaturvedi, V.; Saxena, A.K. Synthesis and biological evaluation of substituted 4-arylthiazol-2-amino derivatives as potent growth inhibitors of replicating Mycobacterium tuberculosis H37RV. Bioorg. Med. Chem. Lett., 2011, 21(18), 5589-5593. doi: 10.1016/j.bmcl.2011.06.076 PMID: 21783364Jeong, K.; Lee, J.; Park, S.; Choi, J.H.; Jeong, D.Y.; Choi, D.H.; Nam, Y.; Park, J.H.; Lee, K.N.; Kim, S.M.; Ku, J.M. Synthesis and in-vitro evaluation of 2-amino-4-arylthiazole as inhibitor of 3D polymerase against foot-and-mouth disease (FMD). Eur. J. Med. Chem., 2015, 102, 387-397. doi: 10.1016/j.ejmech.2015.08.020 PMID: 26301555Shaik, S.P.; Nayak, V.L.; Sultana, F.; Rao, A.V.S.; Shaik, A.B.; Babu, K.S.; Kamal, A. Design and synthesis of imidazo2,1-bthiazole linked triazole conjugates: Microtubule-destabilizing agents. Eur. J. Med. Chem., 2017, 126, 36-51. doi: 10.1016/j.ejmech.2016.09.060 PMID: 27744185Sim, M.; Lee, S.; Han, Y. Synthesis and structural confirmation of the thiazole alkaloids derived from Peganum harmala L. Appl. Sci., 2021, 12(1), 78. doi: 10.3390/app12010078Ali, S.H.; Sayed, A.R. Review of the synthesis and biological activity of thiazoles. Synth. Commun., 2021, 51(5), 670-700. doi: 10.1080/00397911.2020.1854787LigPrep; Schrödinger. LLC: New York, NY, USA, 2021.Madhavi Sastry, G.; Adzhigirey, M.; Day, T.; Annabhimoju, R.; Sherman, W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J. Comput. Aided Mol. Des., 2013, 27(3), 221-234. doi: 10.1007/s10822-013-9644-8 PMID: 23579614Friesner, R.A.; Murphy, R.B.; Repasky, M.P.; Frye, L.L.; Greenwood, J.R.; Halgren, T.A.; Sanschagrin, P.C.; Mainz, D.T. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem., 2006, 49(21), 6177-6196. doi: 10.1021/jm051256o PMID: 17034125Halgren, T.A.; Murphy, R.B.; Friesner, R.A.; Beard, H.S.; Frye, L.L.; Pollard, W.T.; Banks, J.L. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J. Med. Chem., 2004, 47(7), 1750-1759. doi: 10.1021/jm030644s PMID: 15027866QikProp; Schrödinger. LLC: New York, NY, 2019.Hantzsch, A.; Weber, J.H. Ueber verbindungen des thiazols (pyridins der thiophenreihe). Ber. Dtsch. Chem. Ges., 1887, 20(2), 3118-3132. doi: 10.1002/cber.188702002200