TY - JOUR
T1 - Design, synthesis, molecular docking and in vitro evaluation of benzothiazole derivatives as 11β-hydroxysteroid dehydrogenase type 1 inhibitors
AU - Cabrera Pérez, Laura C.
AU - Padilla-Martínez, Itzia I.
AU - Cruz, Alejandro
AU - Correa Basurto, José
AU - Miliar García, Ángel
AU - Hernández Zavala, Argelia A.
AU - Gómez López, Modesto
AU - Rosales Hernández, Martha C.
N1 - Publisher Copyright:
© 2019, Springer Nature Switzerland AG.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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. Graphic abstract: [Figure not available: see fulltext.]
AB - 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. Graphic abstract: [Figure not available: see fulltext.]
KW - 11β-Hydroxysteroid dehydrogenase type 1
KW - Benzothiazole derivatives
KW - Binding affinity
KW - Cortisol
KW - Enzyme inhibition
KW - Obesity
UR - http://www.scopus.com/inward/record.url?scp=85074701842&partnerID=8YFLogxK
U2 - 10.1007/s11030-019-10006-z
DO - 10.1007/s11030-019-10006-z
M3 - Artículo
C2 - 31664610
AN - SCOPUS:85074701842
SN - 1381-1991
VL - 24
SP - 1
EP - 14
JO - Molecular Diversity
JF - Molecular Diversity
IS - 4
ER -