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Design, synthesis, molecular docking and in vitro evaluation of benzothiazole derivatives as 11β-hydroxysteroid dehydrogenase type 1 inhibitors

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Abstract

11-Beta hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates cortisol levels mainly in adipose, hepatic and brain tissues. There is a relationship between the high activity of this enzyme and the development of obesity and metabolic disorders. The inhibition of 11β-HSD1 has been shown to attenuate the development of type 2 diabetes mellitus, insulin resistance, metabolic syndrome and other diseases mediated by excessive cortisol production. In this work, fifteen benzothiazole derivatives substituted with electron-withdrawing and electron-donating groups were designed to explore their affinity for 11β-HSD1 using in silico methods. The results show that (E)-5-((benzo[d]thiazol-2-ylimino)(methylthio)methylamino)-2-hydroxybenzoic acid (C1) has good physicochemical properties and favorable interactions with 11β-HSD1 through hydrogen bonding and hydrophobic interactions in the catalytic site formed by Y183, S170 and Y177. Furthermore, C1 was synthesized and evaluated in vitro and ex vivo using clobenzorex (CLX) as a reference drug in obese Zucker rats. The in vitro results showed that C1 was a better inhibitor of human 11β-HSD1 than CLX. The ex vivo assay results demonstrated that C1 was capable of reducing 11β-HSD1 overexpression in mesenteric adipose tissue. Therefore, C1 was able to decrease the activity and expression of 11β-HSD1 better than CLX.

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References

  1. Su X, Vicker N, Thomas MP, Pradaux-Caggiano F, Halem H, Culler MD, Potter BV (2011) Discovery of adamantyl heterocyclic ketones as potent 11β-hydroxysteroid dehydrogenase type 1 inhibitors. Chem Med Chem 6:1439–1451. https://doi.org/10.1002/cmdc.201100144

    Article  CAS  Google Scholar 

  2. Liu X, Tan XL, Xia M, Wu C, Song J, Wu JJ, Laurence A, Xie QG, Zhang MZ, Liang HF, Zhang BX, Chen XP (2016) Loss of 11βHSD1 enhances glycolysis, facilitates intrahepatic metastasis, and indicates poor prognosis in hepatocellular carcinoma. Oncotarget 7:2038–2053. https://doi.org/10.18632/oncotarget.6661

    Article  Google Scholar 

  3. Seckl JR, Walker BR (2001) Minireview: 11beta-hydroxysteroid dehydrogenase type 1-a tissue-specific amplifier of glucocorticoid action. Endocrinology 142:1371–1376. https://doi.org/10.1210/endo.142.4.8114

    Article  CAS  Google Scholar 

  4. Carvajal CA, Gonzalez AA, Romero DG, González A, Mosso LM, Lagos ET, Hevia-Mdel P, Rosati MP, Perez-Acle TO, Gomez-Sanchez CE, Montero JA, Fardella CE (2003) Two homozygous mutations in the 11beta-hydroxysteroid dehydrogenase type 2 gene in a case of apparent mineralocorticoid excess. J Clin Endocrinol Metab 88:2501–2507. https://doi.org/10.1210/jc.2002-021909

    Article  CAS  Google Scholar 

  5. Yoon DS, Wu SC, Seethala R, Golla R, Nayeem A, Everlof JG, Gordon DA, Hamann LG, Robl JA (2014) Discovery of pyridyl sulfonamide 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors for the treatment of metabolic disorders. Bioorg Med Chem Lett 24:5045–5049. https://doi.org/10.1016/j.bmcl.2014.09.012

    Article  CAS  Google Scholar 

  6. Schnackenberg CG, Costell MH, Krosky DJ, Cui J, Wu CW, Hong VS, Harpel MR, Willette RN, Yue T (2013) Chronic inhibition of 11β-hydroxysteroid dehydrogenase type 1 activity decreases hypertension, insulin resistance, and hypertriglyceridemia in metabolic syndrome. Biomed Res Int. https://doi.org/10.1155/2013/427640

    Article  Google Scholar 

  7. Wiegand S, Richardt A, Remer T, Wudy SA, Tomlinson JW, Hughes B, Grüters A, Stewart PM, Strasburger CJ, Quinkler M (2007) Reduced 11beta-hydroxysteroid dehydrogenase type 1 activity in obese boys. Eur J Endocrinol 157:319–324. https://doi.org/10.1530/EJE-07-0193

    Article  CAS  Google Scholar 

  8. Tomlinson JW (2005) 11Beta-hydroxysteroid dehydrogenase type 1 in human disease: a novel therapeutic target. Minerva Endocrinol 30:37–46

    CAS  Google Scholar 

  9. Czegle I, Margittai F, Senesi S, Benedetti A, Bánhegyi G (2008) Different expression and distribution of 11beta-hydroxysteroid dehydrogenase type 1 in obese and lean animal models of type 2 diabetes. Acta Physiol Hung 95:419–424. https://doi.org/10.1556/APhysiol.95.2008.4.8

    Article  CAS  Google Scholar 

  10. Prasad SS, Prashanth A, Kumar CP, Reddy SJ, Giridharan NV, Vajreswari A (2010) A novel genetically-obese rat model with elevated 11 beta-hydroxysteroid dehydrogenase type 1 activity in subcutaneous adipose tissue. Lipids Health Dis 9:1–6. https://doi.org/10.1186/1476-511X-9-132

    Article  CAS  Google Scholar 

  11. Rosenstock J, Banarer S, Fonseca VA, Inzucchi SE, Sun W, Yao W, Hollis G, Flores R, Levy R, Williams WV, Seckl JR, Huber R (2010) The 11-beta-hydroxysteroid dehydrogenase type 1 inhibitor INCB13739 improves hyperglycemia in patients with type 2 diabetes inadequately controlled by metformin monotherapy. Diabetes Care 33:1516–1522. https://doi.org/10.2337/dc09-2315

    Article  CAS  Google Scholar 

  12. Scott D, Skudlarek JW (2015) 2-Pyridyloxy-4-nitrile orexin receptor antagonists. US Patent WO2013059222 A1, October 13

  13. Argüelles TF, Carrasco PMC, Carrasco PNA, Aguilar CJC, Patiño CSI, Fernández VC, Reyes GG, Flores MFJ (2013) Comparison on the pharmacokinetics and weight reduction of clobenzorex slow release and immediate release formulations in obese patients. Pharmacol Pharm 4:218–221. https://doi.org/10.4236/pp.2013.42030

    Article  CAS  Google Scholar 

  14. Tagawa N, Kubota S, Kato I, Kobayashi Y (2013) Resveratrol inhibits 11β-hydroxysteroid dehydrogenase type 1 activity in rat adipose microsomes. J Endocrinol 218:311–320. https://doi.org/10.1530/JOE-13-0066

    Article  CAS  Google Scholar 

  15. Sorense B, Winn M, Rohde J, Shuai Q, Wang J, Fung S, Monzaon K, Chiou W, Stolarik D, Imade H, Pan L, Deng X, Chovan L, Longenecker K, Judge R, Qin W, Brune M, Camp H, Frevert EU, Jacobson P, Link JT (2007) Adamantane sulfone and sulfonamide 11-beta-HSD1 inhibitors. Bioorg Med Chem Lett 17:527–532. https://doi.org/10.1016/j.bmcl.2006.10.008

    Article  CAS  Google Scholar 

  16. Su X, Vicker N, Ganeshapillai D, Smith A, Purohit A, Reed MJ, Potter BV (2006) Benzothiazole derivatives as novel inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1. Mol Cell Endocrinol 248:214–217. https://doi.org/10.1016/j.mce.2005.10.022

    Article  CAS  Google Scholar 

  17. Cabrera-Pérez LC, Padilla-Martínez II, Cruz A, Mendieta-Wejebe JE, Tamay-Cach F, Rosales-Hernández MC (2016) Evaluation of a new benzothiazole derivative with antioxidant activity in the initial phase of acetaminophen toxicity. Arab J Chem. https://doi.org/10.1016/j.arabjc.2016.02.004

    Article  Google Scholar 

  18. Choy YB, Prausnitz MR (2011) The rule of five for non-oral routes of drug delivery: ophthalmic, inhalation and transdermal. Pharm Res 28:943–948. https://doi.org/10.1007/s11095-010-0292-6

    Article  CAS  Google Scholar 

  19. Cabrera Pérez LC, Gutiérrez Sánchez M, Mendieta Wejebe JE, Hernández Rodríguez M, Fragoso Vázquez MJ, Salazar JR, Correa Basurto J, Padilla Martínez II, Rosales Hernández MC (2017) Novel 5-aminosalicylic derivatives as anti-inflammatories and myeloperoxidase inhibitors evaluated in silico, in vitro and ex vivo. Arab J Chem. https://doi.org/10.1016/j.arabjc.2016.12.026

    Article  Google Scholar 

  20. Hosfield DJ, Wu Y, Skene RJ, Hilgers M, Jennings A, Snell GP, Aertgeerts K (2005) Conformational flexibility in crystal structures of human 11β-hydroxysteroid dehydrogenase type I provide insights into glucocorticoid interconversion and enzyme regulation. J Biol Chem 280:4639–4648. https://doi.org/10.1074/jbc.M411104200

    Article  CAS  Google Scholar 

  21. Nakata T, Fujita A, Umeda M, Yoshida H, Inami H, Masuzaki H, Sawai H (2016) The increased ratio of 11β-hydroxysteroid dehydrogenase type 1 versus 11β-hydroxysteroid dehydrogenase type 2 in chronic periodontitis irrespective of obesity. Springerplus 5:1–7. https://doi.org/10.1186/s40064-016-1679-6

    Article  CAS  Google Scholar 

  22. Favia AD, Masetti M, Recanatini M, Cavalli A (2011) Substrate binding process and mechanistic functioning of type 1 11β-hydroxysteroid dehydrogenase from enhanced sampling methods. PLoS ONE 6:e25375. https://doi.org/10.1371/journal.pone.0025375

    Article  CAS  Google Scholar 

  23. Montgomery RD (1967) Side effects of carbenoxolone sodium: a study of ambulant therapy of gastric ulcer. Gut 8:148–150. https://doi.org/10.1136/gut.8.2.148

    Article  CAS  Google Scholar 

  24. Miguet L, Zhang Z, Barbier M, Grigorov MG (2006) Comparison of a homology model and the crystallographic structure of human 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) in a structure-based identification of inhibitors. J Comput Aided Mol Des 20:67–81. https://doi.org/10.1007/s10822-006-9037-3

    Article  CAS  Google Scholar 

  25. Guo J, Zhou LY, He HP, Leng Y, Yang Z, Hao JX (2012) Inhibition of 11b-HSD1 by tetracyclic triterpenoids from Euphorbia kansui. Molecules 17:11826–11838. https://doi.org/10.3390/molecules171011826

    Article  CAS  Google Scholar 

  26. Goldberg FW, Leach AG, Scott JS, Snelson WL, Groombridge SD, Donald CS, Bennett SNL, Bodin C, Gutierrez PM, Gyte AC (2012) Free-wilson and structural approaches to co-optimizing human and rodent isoform potency for 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors. J Med Chem 55:10652–10661. https://doi.org/10.1021/jm3013163

    Article  CAS  Google Scholar 

  27. Lagos CF, Vecchiola A, Allende F, Fuentes CA, Tichauer JE, Valdivia C, Solari S, Campino C, Tapia-Castillo A, Baudrand R, Villarroel P, Cifuentes M, Owen GI, Carvajal CC, Fardella CE (2014) Identification of novel 11β-HSD1 inhibitors by combined ligand- and structure-based virtual screening. Mol Cell Endocrinol 384:71–82. https://doi.org/10.1016/j.mce.2014.01.011

    Article  CAS  Google Scholar 

  28. Hale C, Véniant M, Wang Z, Chen M, McCormick J, Cupples R, Hickman D, Min X, Sudom A, Xu H, Wang Z, Walker NP (2008) Structural characterization and pharmacodynamic effects of an orally active 11beta-hydroxysteroid dehydrogenase type 1 inhibitor. Chem Biol Drug Des 71:36–44. https://doi.org/10.1111/j.1747-0285.2007.00603.x

    Article  CAS  Google Scholar 

  29. Bohme ST, Engel CK, Farjot G, Gussregen S, Haack T, Tschank G, Ritter K (2013) 1,1-Dioxo-5,6-dihydro-[4,1,2]oxathiazines, a novel class of 11-HSD1 inhibitors for the treatment of diabetes. Bioorg Med Chem Lett 23:4685–4691. https://doi.org/10.1016/j.bmcl.2013.05.102

    Article  CAS  Google Scholar 

  30. Zhou N, Xu Y, Liu X, Wang Y, Peng J, Luo X, Zheng M, Chen K, Jiang H (2015) Combinatorial pharmacophore-based 3D-QSAR analysis and virtual screening of FGFR1. Int J Mol Sci 16:13407–13426. https://doi.org/10.3390/ijms160613407

    Article  CAS  Google Scholar 

  31. Blum A, Favia AD, Maser E (2009) 11beta-Hydroxyesteroid dehydrogenase type 1 inhibitors with oleanan and ursan scaffolds. Mol Cell Endocrinol 301:132–136. https://doi.org/10.1016/j.mce.2008.08.028

    Article  CAS  Google Scholar 

  32. Durebex CV, Deblon N, Caillon A, Andrew R, Altirriba J, Odermatt A, Jeanrenaud FR (2012) Central glucocorticoid administration promotes weight gain and increased 11β-hydroxysteroid dehydrogenase type 1 expression in white adipose tissue. PLoS ONE 7:e34002. https://doi.org/10.1371/journal.pone.0034002

    Article  CAS  Google Scholar 

  33. Sledziński T, Mirowska A, Klimek J (2011) Higher 11-beta-hydroxysteroid dehydrogenase type I gene expression in white adipose tissue in male than female rats. Endokrynol Pol 62:331–334

    Google Scholar 

  34. Mai K, Andres J, Bobbert T, Maser-Gluth C, Möhlig M, Bähr V, Pfeiffer AF, Spranger J, Diederich S (2007) Rosiglitazone decreases 11beta-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue. Clin Endocrinol 67:419–425. https://doi.org/10.1111/j.1365-2265.2007.02903.x

    Article  CAS  Google Scholar 

  35. Mattsson C, Lai M, Noble J, McKinney E, Yau JL, Seckl JR, Walker BR (2003) Obese Zucker rats have reduced mineralocorticoid receptor and 11-beta-hydroxysteroid dehydrogenase type 1 expression in hippocampus-implications for dysregulation of the hypothalamic-pituitary-adrenal axis in obesity. Endocrinology 144:2997–3003. https://doi.org/10.1210/en.2002-221015

    Article  CAS  Google Scholar 

  36. Vélez Marín M, Hurtado Salazar A, Uribe Velásquez LF (2012) Plasma cortisol activity in rats under conditions of chronic stress supplemented with resveratrol. Colomb Med Cali 43:221–225

    Google Scholar 

  37. Livingstone DEW, Walker BR (2003) Is 11β-hydroxysteroid dehydrogenase type 1 a therapeutic target? effects of carbenoxolone in lean and obese zucker rats. J Pharmacol Exp Ther 305:167–172. https://doi.org/10.1124/jpet.102.044842

    Article  CAS  Google Scholar 

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Acknowledgements

We gratefully acknowledge the financial support from PRODUCTOS MEDIX-MÉXICO (Agreement: MEDIX SIP-2014-RE-014), CONACYT (Grant: 254600; 286653), Problemas Nacionales (Grant: 782) and COFAA-SIP/IPN (Grant: 20195089).

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Authors and Affiliations

  1. Laboratorio de Biofísica y Biocatálisis, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Casco de Santo Tomás, 11340, Mexico City, Mexico

    Laura C. Cabrera Pérez, José Correa Basurto, Argelia A. Hernández Zavala & Martha C. Rosales Hernández

  2. Laboratorio de Química Supramolecular y Nanociencias, Unidad Profesional Interdisciplinaria de Biotecnología , Instituto Politécnico Nacional, Av. Acueducto s/n, Barrio La Laguna Ticomán, 07340, Mexico City, Mexico

    Laura C. Cabrera Pérez, Itzia I. Padilla-Martínez & Alejandro Cruz

  3. Laboratorio de Modelado Molecular y Bioinformática, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Casco de Santo Tomás, 11340, Mexico City, Mexico

    José Correa Basurto

  4. Laboratorio de Biología Molecular, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Casco de Santo Tomás, 11340, Mexico City, Mexico

    Ángel Miliar García & Modesto Gómez López

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  1. Laura C. Cabrera Pérez
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  2. Itzia I. Padilla-Martínez
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Cabrera Pérez, L.C., Padilla-Martínez, I.I., Cruz, A. et al. Design, synthesis, molecular docking and in vitro evaluation of benzothiazole derivatives as 11β-hydroxysteroid dehydrogenase type 1 inhibitors. Mol Divers 24, 1–14 (2020). https://doi.org/10.1007/s11030-019-10006-z

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