Fused pyrimidine derivatives R 0515Synthesis Leading to Novel 2,4,6-Trisubstituted Quinazoline Derivatives, Their Antibacterial and Cytotoxic Activity Against THP-1, HL-60 and A375 Cell Lines.-Twelve 2,4,6-Trisubstituted quinazoline derivatives of type (V) are prepared and screened for their antibacterial and cytotoxic effects against the title cell lines. Derivative (Vd) exhibits the highest activity against THP-1 and HL-60 cell lines, whereas (Va) and (Vb) show moderate activity. -(CHANDRIKA, P. M.; YAKAIAH, T.; NARSAIAH*, B.; SRIDHAR, V.; VENUGOPAL, G.; RAO, J. V.; KUMAR, K. P.; MURTHY, U. S. N.; RAO, A. R. R.; Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 48 (2009) 6, 840-847; Fluoroorg. Div., Indian Inst. Chem. Technol., Hyderabad 500 007, India; Eng.) -M. Bohle 43-171
A new series of 3‐(6‐substituted‐benzothiazol‐2‐yl)‐6‐phenyl‐[1, 3]‐oxazinane‐2‐thiones (4a—j) has been synthesised using an appropriate synthetic route (Scheme 1) and characterised by elemental analyses and spectral (IR, 1HNMR, 13C NMR, and EI MS) data. The anticonvulsant activity of all the title compounds (4a—j) was evaluated against Maximal Electroshock (MES) induced seizures and furthermore the most potent compounds were evaluated against subcutaneous pentylenetetrazole (sc PTZ) induced seizures model in mice. The neurotoxicity was assessed using the rotorod procedure. All the test compounds were administered intraperitoneally at various dose levels ranging from 30—200 mg/kg body wt and the median effective dose (ED50), median toxic dose (TD50), and protection index (PI) values were determined (Table 2). Among the compounds tested, the 3‐(6‐dimethylaminobenzothiazol‐2‐yl)‐6‐phenyl‐[1, 3]‐oxazinane‐2‐thiones (4j) was found to be the most potent (ED50: 9.85 and 14.8 in MES model and 12 and 17 in scPTZ model at t = 0.5 h and 4 h, respectively, and TD50 42.8 and 44 at t = 0.5 h and 4 h, respectively, which has been found to be significant at p < 0.01 with respect to reference standard phenytoin) with protection index (PI) 4.85.
With an aim to obtain potent bronchodilators, two series of 5-alkyl-2,3-dihydroimidazo[1,2-c]quinazolines (Va-1), 2,3-dihydroimidazo[1,2-c]quinazolin-5-(6H)-thiones (VIIIa-d) and their oxo-analogues (IXa-d) have been designed. The compounds Va-1 were synthesized by two alternative routes. The former (Method A) based on the dehydrocyclization of 4-(1-hydroxyethyl)-aminoquinazoline (IV) and the latter (Method B) involves the usage of 2-aminobenzonitrile (VI) which on reaction with ethylenediamine leads to the formation of the key intermediate 2-(2-aminophenyl)-4,5-dihydro-1H-imidazoles (VII). Finally the intermediate VII on condensation with different acidanhydrides yielded the title compound V. In general method-A resulted the compound V in quantitatively higher yields. 2,3-Dihydroimidazo[1,2-c]quinazolin-5 (6H)-thiones (VIII) were obtained by condensing VII with carbon disulfide and a further oxidation of VIII gave their corresponding oxo-analogues (IX). The title compounds V, VIII and IX were evaluated for their bronchodilator activity using in vitro and in vivo (standard animal models) methods. All the test compounds exhibited bronchodilatory activity. The structure activity relationship studies indicated good correlation between the nature of the substituent and bronchodilatory activity. In the 5-alkyl substituted compounds V, a longer alkyl chain showed higher bronchodilatory activity. Compounds VIII and IX were found to be less potent and replacement of sulphur with oxygen showed no significant effect on the biological activity. The presence of halogens altered the biological activity in both the series. Among the compounds tested, 9-lodo-5-(n-propyl)-2,3-dihydroimidazo[1,2-c]quinazoline (VI) was found to be the most potent (percentage protection = 87.1%; relative activity = 1.1 compared to the standard aminophylline).
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