Synthesis and Antihyperglycemic Activity of Novel 6,7,8,9 Tetra Hydro-5H-5-Phenyl-2-Benzylidine-3-Substituted Hydrazino Thiazolo (2, 3-B) Quinazoline Derivatives and Analogues

 

Theivendren Panneer Selvam¹* and Palanirajan Vijayaraj Kumar²

¹Department of Biotechnology, Acharya Nagarjuna University, Guntur - 522 510, Andhrapradesh, India.               ²School of Pharmacy, UCSI University, Jalan Menara Gading, 56000 Cheras, Kuala Lumpur, Malaysia.

*Corresponding Author E-mail: tpsphc@gmail.com

ABSTRACT:

As series of heterocycles, 6,7,8,9 Tetra hydro-5H-5-phenyl-2-benzylidine-3-substituted hydrazino thiazolo (2, 3-b) quinazoline 6a-o derivatives were synthesized and tested for Antihyperglycemic activity. Their antihyperglycemic activity was evaluated by Streptozotocin (STZ) and Sucrose-loaded (SLM) model.  All the newly synthesized compounds chemical structures were confirmed by IR, ¹H-NMR, mass spectroscopy and elemental analyses. The results of studies indicate that the compounds 6a, b, d, j, o displayed significant reduction in blood glucose level in streptozotocin and sucrose loaded rat models.

 

 

 

INTRODUCTION:

Quinazolinones and related quinazolines are classes of fused heterocycles that are of considerable interest because of the diverse range of their biological properties. Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia resulting from insufficient   secretion or action of endogenous insulin. The manifestations of diabetes in the hand were much discussed in the 1970s and 1980s^1-5. The prevalence of diabetes is increasing throughout the world and is predicted to increase by two-fold from 150 million in the year 2000 to 300 million by the year 2030⁶. We have found that quinazolines and condensed quinazolines exhibit potent pharmacological activities^7-13. On the other hand, the considerable biological and medicinal activities of thiazole and their derivatives have attracted continuing interest over the years because of their varied biological activities^14,15 recently found 5application in drug  development for the treatment of allergies¹⁶, hypertension¹⁷,  schizophrenia¹⁸, bacterial¹⁹, HIV infections²⁰, hypnotics²¹ and more recently for the treatment of pain²².

 

These observation led to the conception that a novel series of 6,7,8,9 Tetra  hydro-5H-5-phenyl-2-benzylidine-3-substituted hydrazino thiazolo (2, 3-b) quinazoline 6a-o by the reaction of 6,7,8,9 Tetra  hydro-5H-5- phenyl thiazolo (2, 3-b) quinazolin-3(2H)-one 3 with appropriate hydrazine hydrate and ketones ⁄ aldehydes in the presence of anhydrous sodium acetate and glacial acetic acid and their chemical structure were confirmed by IR, ¹H-NMR, mass spectral and elemental analyses. These compounds were screened for their Antihyperglycemic activity

 

RESULTS AND DISCUSSION:

Chemistry

The synthesized series of heterocycles, 6a-o by the reaction of 3 with appropriate hydrazine hydrate and ketones ⁄ aldehydes in the presence of anhydrous sodium acetate and glacial acetic acid as presented in Scheme. The IR, ¹H-NMR, mass spectroscopy and elemental analyses for the new compound is in accordance with the assigned structures. The IR spectrum of compound 3 and 4 showed stretching bands of keto group at 1715-1740 cm^-1. In 5, stretching and bending NH bands of thiazolo quinazoline moiety appear at 3300-3400 cm^-1, 1300-1350 cm^-1 respectively. The absence of keto group absorption at 1715-1740 cm^-1and appearance of a strong intensity band in the IR spectra of compounds 5 in the range of 1610–1655 cm^-1 attributable to C=N provides a strong evidence for the condensation and also confirms the formation of the azomethine 5. The proton magnetic resonance spectra of thiazolo quinazoline and their corresponding derivatives have been recorded in CDCl₃.

 

 

In this 5 NH signal of 6,7,8,9 Tetra hydro-5H-5-phenyl-2-benzylidine-3-hydrazino thiazolo (2, 3-b) quinazoline moiety appear at 7.26 (s) ppm respectively. The position and presence of NH signal in the ¹H-NMR spectra of final compounds confirms the secondary NH proton in thiazolo quinazoline moiety. This clearly envisages that the thiazole-3-one moiety involve in 6,7,8,9 Tetra hydro-5H-5-phenyl-2-benzylidine-3-hydrazino thiazolo (2, 3-b) quinazoline formation.  All these observed facts clearly demonstrate that the 3^rd position of keto group in thiazole ring is converted into secondary amino group as indicated in Scheme and confirms the proposed structure 5. The melting points were taken in open capillary tube and are uncorrected. IR spectra were recorded with KBr pellets (ABB Bomem FT-IR spectrometer MB 104 ABB Limited Bangaluru, India). Proton (¹H) NMR spectra (Bruker 400 NMR spectrometer Mumbai, India) were recorded with TMS as internal references. Mass spectral data were recorded with a quadrupol mass spectrometer (Shimadzu GC MS QP 5000, Chennai, India), and microanalyses were performed using a vario EL V300 elemental analyzer (Elemental Analysen systeme GmbH Chennai, India). The purity of the compounds was checked by TLC on pre-coated SiO₂ gel (HF₂₅₄, 200 mesh) aluminium plates (E.Merck) using ethyl acetate: benzene (1:3) and visualized in UV chamber. IR, ¹H-NMR, mass spectral datas and elemental analyses were consistent with the assigned structures of all the compounds.

 

¹H NMR spectra were recorded for all the targeted compounds. The ¹H NMR spectra were recorded for the representative key intermediate 3. The 6,7,8,9 Tetra hydro-5

H-5-

phenyl thiazolo quinazolin-3-ones. Cream solid; Yield: 83%; mp. 142-144°C; IR cm^-1: 3012 (Cycloalkane C-H ), 3079 (Ar-CH), 1727 (C=O), 1615 (C=C); ¹H-NMR (CDCl₃): δ 6.74-7.76 (m, 5H, Ar-H), 5.75 (s, 1H, H-5), 3.40 (s, 2H, CH_2, thiazole ring), 1.64-2.35 (m, 8H, 4 × CH₂); EI-MS (m/z): 284 (M+); (Calcd for C₁₆H₁₆N₂OS; 284.38). Anal. Calcd for C₁₆H₁₆N₂OS; C, 67.58; H, 5.67; N, 9.85; Found: C, 67.60; H, 5.74; N, 9.90.

 

4. 6,7,8,9 Tetra  hydro-5H-5-phenyl-2-benzylidine thiazolo (2, 3-b) quinazolin-3(2H)-one.

Pale Yellow solid; Yield: 75%; mp. 146-148°C; IR cm^-1: 3100 (Cycloalkane  C-H ), 3059 (Ar-CH), 1742 (C=O), 1613 (C=C); ¹H-NMR (CDCl₃): δ 6.82-7.46 (m, 10H, Ar-H), 5.86 (s, 1H, H-5), 6.57 (s, 1H, =CH), 1.82-2.24 (m, 8H, 4 × CH₂); EI-MS (m/z): 372 (M+); (Calcd for C₂₃H₂₀N₂OS; 372.48). Anal. Calcd for C₂₃H₂₀N₂OS; C, 74.16; H, 5.41; N, 7.52; Found: C, 74.26; H, 5.31; N, 7.44.

 

5. 6,7,8,9 Tetra  hydro-5H-5-phenyl-2-benzylidine-3-hydrazino thiazolo (2, 3-b) quinazoline.

Dark brown solid; Yield: 69%; mp. 169-171°C; IR cm^-1: 3076 (Cycloalkane  C-H ), 3144 (Ar-CH), 1618 (C=C); 3378 (N-H); 1341 (N-H); 1654 (C=N); ¹H-NMR (CDCl₃): δ 6.74-7.86 (m, 10H, Ar-H), 5.56 (s, 1H, H-5), 6.38 (s, 1H, =CH), 7.26 (s, 2H, NH₂), 1.90-2.42 (m, 8H, 4 × CH₂); EI-MS (m/z): 386 (M+); (Calcd for C₂₃H₂₂N₄S; 386.51). Ana. Calcd for C₂₃H₂₂N₄S; C, 71.47; H, 5.74; N, 14.50; Found: C, 71.42; H, 5.68; N, 14.66.

 

6a. 6,7,8,9 Tetra hydro-5H-5-phenyl-2-benzylidine-3-(N´-2-butylidene-hydrazino) thiazolo (2, 3-b) quinazoline.

Yellow solid; Yield: 78%; mp. 176-178°C; IR cm^-1: 2912 (Cycloalkane  C-H ), 3078 (Ar-CH),  1534 (C=C); 2868 (C-H in CH₃); 1656 (C=N); ¹H-NMR (CDCl₃): δ 6.82-7.46 (m, 10H, Ar-H), 5.18 (s, 1H, H-5), 6.18 (s, 1H, =CH), 1.80-2.32 (m, 8H, 4 × CH₂), 1.4 (q, 2H, CH₂CH₃), 1.82 (t, J=7.0 Hz, 3H, CH₂CH₃), 2.64 (s, 3H, CH₃); EI-MS (m/z): 440 (M+); (Calcd for C₂₇H₂₈N₄S; 440.60). Ana. Calcd for C₂₇H₂₈N₄S; C, 73.60; H, 6.41; N, 12.72; Found: C, 73.56; H, 6.49; N, 12.78.

 

 

6b. 6,7,8,9 Tetra hydro-5H-5-phenyl-2-benzylidine-3- (N´-3-pentylidene-hydrazino) thiazolo (2, 3-b) quinazoline.

Pale yellow crystals; Yield: 72%; mp. 164-166°C; IR cm^-1: 2987 (Cycloalkane, C-H ), 3065 (Ar-CH),  1541 (C=C); 2833 (C-H in CH₃); 1649 (C=N); ¹H-NMR (CDCl₃): δ 6.44-7.88 (m, 10H, Ar-H), 5.08 (s, 1H, H-5), 6.20 (s, 1H, =CH), 1.76-2.46 (m, 8H, 4 × CH₂), 1.52 (q, 4H, CH₂CH₃),

1.92 (t, J=7.0 Hz, 6H, CH₂CH₃); EI-MS (m/z): 454 (M+); (Calcd for C₂₈H₃₀N₄S; 454.63). Ana. Calcd for C₂₈H₃₀N₄S; C, 73.97; H, 6.65; N, 12.32; Found: C, 73.85; H, 6.68; N, 12.34.

 

6c. 6,7,8,9 Tetra hydro-5H-5-phenyl-2-benzylidine-3-(N´-2-pentylidene-hydrazino) thiazolo (2, 3-b) quinazoline.

Creamy crystals; Yield: 68%; mp. 178-180°C; IR cm^-1: 2952 (Cycloalkane  C-H ), 3068 (Ar-CH),  1544 (C=C); 2870 (C-H in CH₃); 1660 (C=N); ¹H-NMR (CDCl₃): δ 6.72-7.36 (m, 10H,

Ar-H), 5.22 (s, 1H, H-5), 6.24 (s, 1H, =CH), 1.82-2.36 (m, 8H, 4 × CH₂), 0.91 (t, 2H, CH₂ CH₂CH₃), 1.33 (sext, 2H, CH₂ CH₂CH₃), 2.84 (t, 3H, CH₂ CH₂CH₃), 2.68 (s, 3H, CH₃); EI-MS (m/z): 454 (M+); (Calcd for C₂₈H₃₀N₄S; 454.63). Ana. Calcd for C₂₈H₃₀N₄S; C, 73.97; H, 6.65; N, 12.32; Found: C, 73.99; H, 6.63; N, 12.28.

 

6d. 6,7,8,9 Tetra hydro-5H-5-phenyl-2-benzylidine-3-(N´-cyclohexylidene-hydrazino) thiazolo (2, 3-b) quinazoline.

Yellow crystals; Yield: 82%; mp. 182-184°C; IR cm^-1: 2924 (Cycloalkane  C-H ), 3028 (Ar-CH),  1544 (C=C); 1666 (C=N); ¹H-NMR (CDCl₃): δ 6.92-7.86 (m, 10H, Ar-H), 5.26 (s, 1H, H-5), 6.24 (s, 1H, =CH), 1.60-2.04 (m, 18H, 9 × CH₂); EI-MS (m/z): 466 (M+); (Calcd for C₂₉H₃₀N₄S; 466.64). Ana. Calcd for C₂₉H₃₀N₄S; C, 74.64; H, 6.48; N, 12.01; Found: C, 74.68; H, 6.52; N, 12.11.

 

6e. 6,7,8,9 Tetra hydro -5H- 5- phenyl -2- benzylidine -3- (N´-1-phenylethylidene-hydrazino) thiazolo (2, 3-b) quinazoline.

Yellow  solid; Yield: 84%; mp. 146-148°C; IR cm^-1: 2928 (Cycloalkane  C-H ), 3098 (Ar-CH),  1542 (C=C); 2918 (C-H in CH₃); 1606 (C=N); ¹H-NMR (CDCl₃): δ 6.62-7.16 (m, 15H, Ar-H), 5.06 (s, 1H, H-5), 6.06 (s, 1H, =CH), 1.74-2.38 (m, 8H, 4 × CH₂), 2.74 (s, 3H, CH₃); EI-MS (m/z): 488 (M+); (Calcd for C₃₁H₂₈N₄S; 488.65). Ana. Calcd for C₃₁H₂₈N₄S; C, 76.20; H, 5.78; N, 11.47; Found: C, 76.30; H, 5.82; N, 11.49.

 

6f. 6,7,8,9 Tetra hydro-5H-5-phenyl-2-benzylidine-3-(N´-1-oxo-indolin-2-one-3-ylidene-hydrazino) thiazolo (2, 3-b) quinazoline.

Pale yellow solid; Yield: 70%; mp. 156-158°C; IR cm^-1: 2934 (Cycloalkane  C-H ), 3086 (Ar-CH),  1538 (C=C); 1616 (C=N), 1338 (C-N), 1726 (C=O); ¹H-NMR (CDCl₃): δ 6.60-7.18 (m, 14H, Ar-H), 5.16 (s, 1H, H-5), 6.12 (s, 1H, =CH), 1.78-2.32 (m, 8H, 4 × CH₂), 8.06 (s, 1H, NH); EI-MS (m/z): 515 (M+); (Calcd for C₃₁H₂₅N₅OS; 515.63). Ana. Calcd for C₃₁H₂₅N₅OS; C, 72.21; H, 4.89; N, 13.58; Found: C, 72.18; H, 4.92; N, 13.48.

 

6g. 6,7,8,9 Tetra hydro-5H-5-phenyl-2-benzylidine-3-( N´-benzylidene-hydrazino) thiazolo (2, 3-b) quinazoline.

Creamy crystals; Yield: 72%; mp. 159-160°C; IR cm^-1: 2934 (Cycloalkane  C-H ), 3048 (Ar-CH),  1568 (C=C);  1608 (C=N); ¹H-NMR (CDCl₃): δ 6.90-7.68 (m, 15H, Ar-H), 5.22 (s, 1H, H-5), 6.34 (s, 1H, =CH), 8.1 (s, 1H, CH), 1.61-2.10 (m, 8H, 4 × CH₂); EI-MS (m/z): 474 (M+); (Calcd for C₃₀H₂₆N₄S; 474.62). Ana. Calcd for C₃₀H₂₆N₄S; C, 75.92; H, 5.52; N, 11.80; Found: C, 75.96; H, 5.58; N, 11.90.

 

6h. 6,7,8,9 Tetra hydro-5H-5-phenyl-2-benzylidine-3-(N´-(2-chloro-benzylidene hydrazino) thiazolo (2, 3-b) quinazoline.

Brown crystals; Yield: 77%; mp. 162-164°C; IR cm^-1: 2926 (Cycloalkane  C-H ), 3056 (Ar-CH),  1562 (C=C); 1598 (C=N), 816 (C-Cl); ¹H-NMR (CDCl₃): δ 6.80-7.58 (m, 14H, Ar-H), 5.32 (s, 1H, H-5), 6.38 (s, 1H, =CH), 8.12 (s, 1H, CH), 1.66-2.20 (m, 8H, 4 × CH₂); EI-MS (m/z): 511 (M+2); (Calcd for C₃₀H₂₅ClN₄S; 509.60). Ana. Calcd for C₃₀H₂₅ClN₄S; C, 70.78; H, 4.95; N, 11.01; Found: C, 70.80; H, 4.99; N, 11.11.

 

6i. 6,7,8,9 Tetra  hydro-5H-5-phenyl-2-benzylidine-3-(N´-(4-chloro-benzylidene hydrazino) thiazolo (2, 3-b) quinazoline.

Yellow solid; Yield: 79%; mp. 144-146°C; IR cm^-1: 2928 (Cycloalkane  C-H ), 3058 (Ar-CH),  1566 (C=C); 1590 (C=N), 826 (C-Cl); ¹H-NMR (CDCl₃): δ 6.76-7.52 (m, 14H, Ar-H), 5.34 (s, 1H, H-5), 6.36 (s, 1H, =CH), 8.22 (s, 1H, CH), 1.68-2.28 (m, 8H, 4 × CH₂); EI-MS (m/z): 511 (M+2); (Calcd for C₃₀H₂₅ClN₄S; 509.60). Ana. Calcd for C₃₀H₂₅ClN₄S; C, 70.78; H, 4.95; N, 11.01; Found: C, 70.82; H, 4.98; N, 11.08.

 

6j. 6,7,8,9 Tetra hydro-5H-5-phenyl-2-benzylidine-3-(N´-(2-nitro-benzylidene hydrazino) thiazolo (2, 3-b) quinazoline.

Creamy crystals; Yield: 77%; mp. 166-168°C; IR cm^-1: 2930 (Cycloalkane  C-H ), 3048 (Ar-CH),  1542 (C=C); 1584 (C=N); ¹H-NMR (CDCl₃): δ 6.72-7.58 (m, 14H, Ar-H), 5.24 (s, 1H, H-5), 6.22 (s, 1H, =CH), 8.44 (s, 1H, CH), 1.52-2.18 (m, 8H, 4 × CH₂); EI-MS (m/z): 519 (M+); (Calcd for C₃₀H₂₅N₅O₂S; 519.62). Ana. Calcd for C₃₀H₂₅N₅O₂S; C, 69.34; H, 4.85; N, 13.48; Found: C, 69.38; H, 4.89; N, 13.54.

 

6k. 6,7,8,9 Tetra hydro-5H-5-phenyl-2-benzylidine-3-(N´-(4-nitro-benzylidene hydrazino) thiazolo (2, 3-b) quinazoline.

Pale yellow crystals; Yield: 71%; mp. 142-144°C; IR cm^-1: 2922 (Cycloalkane  C-H ), 3066 (Ar-CH),  1538 (C=C);  1562 (C=N); ¹H-NMR (CDCl₃): δ 6.68-7.52 (m, 14H, Ar-H), 5.32 (s, 1H, H-5), 6.12 (s, 1H, =CH), 8.32 (s, 1H, CH), 1.40-2.20 (m, 8H, 4 × CH₂); EI-MS (m/z): 519 (M+); (Calcd for C₃₀H₂₅N₅O₂S; 519.62). Ana. Calcd for C₃₀H₂₅N₅O₂S; C, 69.34; H, 4.85; N, 13.48; Found: C, 69.40; H, 4.82; N, 13.46.

 

6l. 6,7,8,9 Tetra hydro-5H-5-phenyl-2-benzylidine-3-(N´-(4-methoxy-benzylidene hydrazino) thiazolo (2, 3-b) quinazoline.

Brown solid; Yield: 75%; mp. 150-152°C; IR cm^-1: 2968 (Cycloalkane  C-H ), 3050 (Ar-CH),  1550 (C=C); 1560 (C=N); ¹H-NMR (CDCl₃): δ 6.75-7.56 (m, 14H, Ar-H), 5.22 (s, 1H, H-5), 6.35 (s, 1H, =CH), 8.44 (s, 1H, CH), 1.80-2.60 (m, 8H, 4 × CH₂), 3.73 (s, 3H, OCH₃); EI-MS (m/z): 504 (M+); (Calcd for C₃₁H₂₈N₄OS; 504.65). Ana. Calcd for C₃₁H₂₈N₄OS; C, 73.78; H, 5.59; N, 11.10; Found: C, 73.82; H, 5.63; N, 11.14.

 

6m. 6,7,8,9 Tetra hydro-5H-5-phenyl-2-benzylidine-3-(N´-(2-methyl-benzylidene hydrazino) thiazolo (2, 3-b) quinazoline.

Creamy crystals; Yield: 80%; mp. 136-138°C; IR cm^-1: 2972 (Cycloalkane  C-H ), 3054 (Ar-CH),  1548 (C=C); 1568 (C=N); ¹H-NMR (CDCl₃): δ 6.70-7.52 (m, 14H, Ar-H), 5.33 (s, 1H, H-5), 6.36 (s, 1H, =CH), 8.64 (s, 1H, CH), 1.88-2.66 (m, 8H, 4 × CH₂), 3.73 (s, 3H, CH₃); EI-MS (m/z): 488 (M+); (Calcd for C₃₁H₂₈N₄S; 488.65). Ana. Calcd for C₃₁H₂₈N₄S; C, 76.20; H, 5.78; N, 11.47; Found: C, 76.24; H, 5.82; N, 11.49.

 

6n. 6,7,8,9 Tetra hydro-5H-5-phenyl-2-benzylidine-3-(N´-(4-methyl-benzylidene hydrazino) thiazolo (2, 3-b) quinazoline.

Creamy crystals; Yield: 82%; mp. 148-150°C; IR cm^-1: 2976 (Cycloalkane  C-H ), 3060 (Ar-CH),  1554 (C=C); 1574 (C=N); ¹H-NMR (CDCl₃): δ 6.77-7.57 (m, 14H, Ar-H), 5.38 (s, 1H, H-5), 6.40 (s, 1H, =CH), 8.60 (s, 1H, CH), 1.90-2.70 (m, 8H, 4 × CH₂), 3.75 (s, 3H, CH₃); EI-MS (m/z): 488 (M+); (Calcd for C₃₁H₂₈N₄S; 488.65). Ana. Calcd for C₃₁H₂₈N₄S; C, 76.20; H, 5.78; N, 11.47; Found: C, 76.26; H, 5.88; N, 11.52.

 

6o. 6,7,8,9 Tetra hydro-5H-5-phenyl-2-benzylidine-3-(N´-(2-phenyl-benzylidene hydrazino) thiazolo (2, 3-b) quinazoline.

Pale brown solid; Yield: 78%; mp. 152-154°C; IR cm^-1 : 2988 (Cycloalkane  C-H ), 3088 (Ar-CH),  1572 (C=C); 1584 (C=N); ¹H-NMR (CDCl₃): δ 6.90-7.70 (m, 20H, Ar-H), 5.36 (s, 1H, H-5), 6.32 (s, 1H, =CH), 1.84-2.52 (m, 8H, 4 × CH₂); EI-MS (m/z): 550 (M+); (Calcd for C₃₆H₃₀N₄S; 550.72). Ana. Calcd for C₃₆H₃₀N₄S; C, 78.51; H, 5.49; N, 10.17; Found: C, 78.55; H, 5.54; N, 10.22.

Antihyperglycemic activity:

Among the 15 screened compounds only 6a, b, d, j, o demonstrated antihyperglycemic activity in STZ model while two additional compounds 6e and 6p, displayed blood glucose lowering activity at 100 mg/kg dose in SLM model. In these compounds, 6,7,8,9 Tetra hydro-5H-5-phenyl-2-benzylidine-3-(N´-2-butylidene-hydrazino) thiazolo (2, 3-b) quinazoline (6a) reduced blood glucose level to 58 and 77% in STZ and SLM models, respectively. The other active compound 6,7,8,9 Tetra hydro-5H-5-phenyl-2-benzylidine-3- (N´-3-pentylidene-hydrazino) thiazolo (2, 3-b) quinazoline (6b) also displayed moderate antihyperglycemic activity (21.5%), possibly due to its slow transformation to the highly active metabolite 6,7,8,9 Tetra hydro-5H-5-phenyl-2-benzylidine-3-(N´-2-butylidene-hydrazino) thiazolo (2, 3-b) quinazoline (6a) but was found inactive in SLM model. A Compound with 2-phenyl-benzylidene hydrazino substituent at position 3 in thiazole ring (6o) displayed a significant blood glucose lowering activity (52.9%) in SLM model while only12.4% reduction in blood glucose level in STZ model. It is evident fromTable1 that, the presence of 2-pentylidene-hydrazino, 2-chloro-benzylidene and 4-methyl-benzylidene in thiazole ring (6 c, h, n) caused a complete loss of antihyperglycemic activity. Two compounds, 6,7,8,9 Tetra hydro-5H-5-phenyl-2-benzylidine-3- (N´-3-pentylidene-hydrazino) thiazolo (2, 3-b) quinazoline (6b) and 6,7,8,9 Tetra hydro-5H-5-phenyl-2-benzylidine-3-(N´-cyclohexylidene-hydrazino) thiazolo (2, 3-b) quinazoline (6d), reduced blood glucose level by14.8 and 13.4%, respectively, in STZ model while latter demonstrated significant activity (38%) in SLM model. Metformin and glybenclamide were used as standard antidiabetic drug in both the models.

 

Table1. Invivo antihyperglycemic activity of various quinazoline derivatives (6a–o) in streptozotocin (STZ) and sucrose-loaded (SLM) rat models.

Compounds	% Blood sugar lowering activity (100mg/kg)
	STZ model	SLM model
6a	58.0	77.0
6b	14.8	33.0
6c	NIL	NIL
6d	13.4	NIL
6e	NIL	NIL
6f	NIL	NIL
6g	NIL	NIL
6h	NIL	NIL
6i	NIL	NIL
6j	21.5	NIL
6k	NIL	NIL
6l	NIL	NIL
6m	NIL	NIL
6n	NIL	NIL
6o	12.4	52.9
Metformin	19.1	12.9
Glybenclamide	29.0	33.7

 

MATERIALS AND METHODS:

Chemistry:

The synthetic strategy leading to the key intermediate and the target compounds are illustrated in the scheme. 6,7,8,9 Tetra hydro-5H-5-(2'-hydroxy phenyl) thiazolo (2, 3-b) quinazolin-3(2H)-one 3 prepared by the equimolar quantities of each (0.039 mol) of cyclohexanone and benzaldehyde (0.039 mol) were taken in a beaker, to this sodium hydroxide solution was added to make the solution alkaline; this was shaken and kept aside. The solid thus obtained, was filtered, washed with water and recrystallized from absolute ethanol. A mixture of 2-benzylidine cyclohexanone ring 1 (0.039 mol) thiourea (0.03 mol) and potassium hydroxide (2.5g) in ethanol (100 ml) was heated under reflux for 3h. The reaction mixture was concentrated to half of its volume, dilute with water, then acidified with dilute acetic acid and kept overnight. The solid thus obtained, was filtered, washed with water and recrystallized from ethanol to give 3, 4, 5, 6, 7, 8-hexahydro-4-phenyl quinazolin-2-thione 2. The chloroacetic acid (0.096 mol) was melted on a water bath and thione (0.009 mol) added to it portion wise to maintain its homogeneity. The homogeneous mixture was further heated on a water bath for 30 min and kept overnight. The solid thus obtained was washed with water until neutralized and crystallized from ethanol to give 6,7,8,9 Tetra  hydro-5H-5-phenyl thiazolo (2, 3-b) quinazolin-3(2H)-one 3 [13]. A mixture of 3 (0.002 mol), benzaldehyde (0.002 mol) and anhydrous sodium acetate (0.002 mol) in glacial acetic acid (10 ml) was heated under reflux for 4h. The reaction mixture was kept overnight and the solid, thus separated, was filtered, washed with water and recrystallized from ethanol to furnish of 6,7,8,9 Tetra  hydro-5H-5-phenyl-2-benzylidine thiazolo (2,3-b) quinazolin-3(2H)-one 4. Euqimolar quantities (0.004 mol) of compound 4 hydrazine hydrate (99%) (0.004 mol) were dissolved in 10ml of warm ethanol and refluxed for 30 min. After standing for approximately 24h at room temperature, the product were separated by filtration, vaccum dried and recrystallized from warm ethanol to yields 6,7,8,9 Tetra  hydro-5H-5-phenyl-2-benzylidine-3-hydrazino thiazolo (2, 3-b) quinazoline 5. A mixture of 5 (0.004 mol) and appropriate ketones ⁄ aldehydes (0.004 mol) in glacial acetic acid was refluxed for 38 h. The reaction mixture was poured into ice water. The solid obtained was recrystallized from ethanol to yields 6,7,8,9 Tetra  hydro-5H-5-phenyl-2-benzylidine-3-substituted hydrazino thiazolo (2, 3-b) quinazoline 6a-o.

Most of the synthesized compounds were evaluated for invivo antihyperglycemic activity in male Sprague–Dawley rats of body weight (160 20g) in two different models.

 

Streptozotocin (STZ) model:

A solution of streptozotocin (60mg/kg) in 100 mM citrate buffer, pH 4.5 was prepared and calculated amount of the fresh solution was dosed to overnight fasted rats (60mg/kg) intraperitoneally. The blood sugar level was measured after 48 h by glucometer. Animals showing 200–400mg/dL were selected for antidiabetic screening. The diabetic animals were divided into groups of six animals each. Rats of experimental group were administered a suspension of the desired test sample (prepared in1% gum acacia) orally (100 mg/kg body weight). Controlled group animals were also fed with 1% gum acacia. The blood glucose levels were measured at 1-, 2-, 3-, 4-, 5-, 6-, 7- and 24 h intervals. The % fall in blood glucose from 1to24 h by test sample was calculated according to the area under curve (AUC) method. The average fall in AUC in experimental group compared to control group provided % antihyperglycemic activity.

 

Sucrose-loaded (SLM) model:

Overnight fasted male Sprague–Dawleyrats were used for sucrose-loaded experiment. Blood was collected initially and there after test compounds were given to the test group consisting of five rats by oral gavage at a dose of 100mg/kg body weight. After half an hour post-test treatment, a sucrose load of 10 gm/kg body weight was given to each rat. Blood was collected at 30, 60, 90 and 120 min post sucrose load. The % fall in blood glucose level was calculated according to the AUC method.

 

ACKNOWLEDGEMENT:

We are grateful to Management of DCRM Pharmacy College and Prof. N.Ramesh Kumar, Chemistry Department, C.L.Baid Metha College of Pharmacy, Chennai, India for facilities and support.

 

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Received on 13.03.2010       Modified on 23.03.2010

Accepted on 12.05.2010      © RJPT All right reserved