Synthesis, Anti-Diabetic and Renoprotective Activity of Some New Benzazole, Thiazolidin-4-one and Azetidin-2-one Derivatives

A new series of benzazole, thiazolidinone and azetidin-2-one derivatives incorporating to pyrazole moiety were synthesized by condensation of 1,3-diphenyl-1H-pyrazol-4-carboxaldehyde with different nucleophiles. The structures of the newly synthesized compounds were confirmed by analytical and spectral methods. Some of these compounds were evaluated for their anti-hyperglycemic and renoprotective activities. Three compounds showed remarkable anti-diabetic potency, whereas other five compounds showed significant renoprotective activity.

Keywords:
anti-diabetic; renoprotective; pyrazole; thiazolidine-4-one; azetidine-2-one

Authorship

Ahmed Abdou O. Abeed

Department of Chemistry, Faculty of Science, Assiut University, 71516 Assiut, EgyptAssiut UniversityEgyptAssiut, EgyptDepartment of Chemistry, Faculty of Science, Assiut University, 71516 Assiut, Egypt

Mohamed Salah K. Youssef ^** e-mail: salah_kamel2000@yahoo.com

Rehab Hegazy

Department of Pharmacology, Medical Division, National Research Centre, 17156 Giza, EgyptNational Research CentreEgyptGiza, EgyptDepartment of Pharmacology, Medical Division, National Research Centre, 17156 Giza, Egypt

* e-mail: salah_kamel2000@yahoo.com

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Figures

Figures (8)

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Figure 1
The pharmacophore hybridization process. (A) Thiazolidine-4-one ring; (B) azetidin-2-one; (C) pyrazole ring.

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Scheme 1
Reagents and conditions: (i) ethanol, AcOH, 5 h; (ii) thioglycolic acid, DMF, ZnCl₂, reflux 8 h; (iii) chloroacetyl chloride, dioxane, TEA, stirring then reflux 8 h.

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Scheme 2
Reagents and conditions: (i) ethanol, AcOH, 5 h; (ii) thioglycolic acid, DMF, ZnCl₂, reflux 8 h; (iii) chloroacetyl chloride, dioxane, TEA, stirring then reflux 8 h.

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Scheme 3
Reagents and conditions: (i) ethanol, AcOH, 5 h; (ii) thioglycolic acid, DMF, ZnCl₂, reflux 8 h; (iii) chloroacetyl chloride, dioxane, TEA, stirring then reflux 8 h.

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Figure 2
Serum glucose levels of compounds 7b, 12b and 13b. Normal: rats treated with the vehicle; STZ: rats treated with STZ; STZ-Glic: rats treated with STZ and Glic; STZ-T(x), rats treated with STZ and the tested agent of the corresponding number (x). a: Significantly different from Normal group at p < 0.05; b: significantly different from STZ group at p < 0.05.

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Figure 3
Serum cholesterol and triglyceride (TG) levels of compounds 7b, 12b and 13b. Normal: rats treated with the vehicle; STZ: rats treated with streptozotocin; STZ-Glic: rats treated with streptozotocin and Glic; STZ-T(x): rats treated with STZ and the tested agent of the corresponding number (x). a: Significantly different from normal group at p < 0.05; b: significantly different from STZ group at p < 0.05; c: significantly different from STZ-Glic group at p < 0.05; d: significantly different from the other STZ-T(x) groups at p < 0.05.

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Figure 4
Serum levels of urea, creatinine and total protein of compounds 3a, 3b, 5a, 7a, 8a, and 8b. Normal: rats with sham operation; I/R ARF: rats with ischemia/reperfusion-induced acute renal failure; I/R-T(x): rats with ischemia/reperfusion-induced acute renal failure treated with the tested compounds of the corresponding number (x). a: Significantly different from normal group at p < 0.05; b: significantly different from I/R ARF group at p < 0.05.

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Figure 5
Renal contents of GSH, MDA, and NOx of compounds 3a, 3b, 5a, 7a, 8a, and 8b. Normal: rats with sham operation; I/R ARF: rats with ischemia/reperfusion-induced acute renal failure; I/R-T(x): rats with ischemia/reperfusion-induced acute renal failure treated with the tested agent of the corresponding number (x). a: Significantly different from normal group at p < 0.05; b: significantly different from I/R ARF group at p < 0.05.

Figure 1 The pharmacophore hybridization process. (A) Thiazolidine-4-one ring; (B) azetidin-2-one; (C) pyrazole ring.

Scheme 1 Reagents and conditions: (i) ethanol, AcOH, 5 h; (ii) thioglycolic acid, DMF, ZnCl₂, reflux 8 h; (iii) chloroacetyl chloride, dioxane, TEA, stirring then reflux 8 h.

Scheme 2 Reagents and conditions: (i) ethanol, AcOH, 5 h; (ii) thioglycolic acid, DMF, ZnCl₂, reflux 8 h; (iii) chloroacetyl chloride, dioxane, TEA, stirring then reflux 8 h.

Scheme 3 Reagents and conditions: (i) ethanol, AcOH, 5 h; (ii) thioglycolic acid, DMF, ZnCl₂, reflux 8 h; (iii) chloroacetyl chloride, dioxane, TEA, stirring then reflux 8 h.

Figure 2 Serum glucose levels of compounds 7b, 12b and 13b. Normal: rats treated with the vehicle; STZ: rats treated with STZ; STZ-Glic: rats treated with STZ and Glic; STZ-T(x), rats treated with STZ and the tested agent of the corresponding number (x). a: Significantly different from Normal group at p < 0.05; b: significantly different from STZ group at p < 0.05.

Figure 3 Serum cholesterol and triglyceride (TG) levels of compounds 7b, 12b and 13b. Normal: rats treated with the vehicle; STZ: rats treated with streptozotocin; STZ-Glic: rats treated with streptozotocin and Glic; STZ-T(x): rats treated with STZ and the tested agent of the corresponding number (x). a: Significantly different from normal group at p < 0.05; b: significantly different from STZ group at p < 0.05; c: significantly different from STZ-Glic group at p < 0.05; d: significantly different from the other STZ-T(x) groups at p < 0.05.

Figure 4 Serum levels of urea, creatinine and total protein of compounds 3a, 3b, 5a, 7a, 8a, and 8b. Normal: rats with sham operation; I/R ARF: rats with ischemia/reperfusion-induced acute renal failure; I/R-T(x): rats with ischemia/reperfusion-induced acute renal failure treated with the tested compounds of the corresponding number (x). a: Significantly different from normal group at p < 0.05; b: significantly different from I/R ARF group at p < 0.05.

Figure 5 Renal contents of GSH, MDA, and NOx of compounds 3a, 3b, 5a, 7a, 8a, and 8b. Normal: rats with sham operation; I/R ARF: rats with ischemia/reperfusion-induced acute renal failure; I/R-T(x): rats with ischemia/reperfusion-induced acute renal failure treated with the tested agent of the corresponding number (x). a: Significantly different from normal group at p < 0.05; b: significantly different from I/R ARF group at p < 0.05.

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Synthesis, Anti-Diabetic and Renoprotective Activity of Some New Benzazole, Thiazolidin-4-one and Azetidin-2-one Derivatives

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[1] * e-mail: salah_kamel2000@yahoo.com