Synthesis and QSAR Study of Some HDL Cholesterol Increasing Quinazolinone Derivatives

We describe here an easy and efficient method to obtain s-alkylated derivatives of thio-quinazolinone using different alkylating agents via a solvent-free microwave-assisted method. The alkylated thio quinazolinones were further sequentially condensed with hydrazine hydrate and different aromatic aldehydes to get the hydrazones, which were studied for QSAR. The synthesized compounds were subjected to a prediction of biological activities. A software application (PASS) was used for this purpose. The relationship between structure and different biological activities was studied and the different derivatives were recommended for the screening of some specific activities like anti-tuberculosic, anti-mycobacterial and HDL cholesterol increasing activities.


Introduction
In recent years the use of microwave irradiation in organic reactions is rapidly increasing because of the short reaction time, operational simplicity and formation of clean reaction products.Avoiding use of organic solvent during the reactions in organic synthesis leads to a clean, efficient and economical technology (green chemistry).It has been commonly employed as thermal energy source in various organic reactions 1 .The use of domestic microwave oven in this regard is now a well-established procedure in MORE 2 (microwave induced organic reaction enhancement) chemistry.It has been reported that the rate of variety of organic reactions such as Diels-Alder 3 , ene 4 , Claisen reaction 5 , oxidation 6 , reduction 7 , diacetylation 8 , deacetylation 9 , deoximation 10 , esterification 11 , hydrolysis of ester 12 , Doebner condensation 13 , Knoevenagel condensation 14 coulds be enhanced by microwave irradiation.Several workers have reported the alkylation of N-containing heterocycles.In this regard microwave (MW) activation have been successfully applied in the synthesis of such derivatives [15][16][17] .
Quinazoline derivatives are of special importance because of their versatile biological & pharmacological activities [18][19][20] , especially anti-inflammatory [21][22][23] , anticonvulsant 24 ,hypnotic 25 , anthemintic 26 , hypo-tensive 27 , antibacterial 28 agents etc.In the present work, s-alkylated derivatives of thio-quinazolinone were obtained using Ethyl chloroacetate via a solvent-free microwave-assisted method.The alkylated thio quinazolinones were further sequentially condensed with hydrazine hydrate and different aromatic aldehydes to get the hydrazides, which were studied for QSAR.The synthesized compounds were subjected to a prediction of biological activities.A software application (PASS) 29 was used for this purpose.The relationship between structure and different biological activities was studied and the different derivatives were recommended for the screening of some specific activities.

Experimental
All m.ps.were determined in open capillary tubes and are uncorrected.IR spectra were recorded in KBr on Shimadzu IR-437 spectrophotometer and PMR spectra in CDCl 3 and DMSO-d 6 on Perkin-Elmer R-32 spectrometer using TMS as an internal standard.The purity of the compounds was checked by TLC.Microwave irradiation was carried out in the domestic microwave oven by SHARP.

2-Mercapto-3-o-tolyl-3H-quinazolin-4-one (I a)
2-Mercapto-3-o-tolyl-3H-quinazolin-4-one (I a) was synthesized by a reported method 30 as follows.The mixture of 2-methyl aniline (0.1 mole) was dissolved in benzene (12 mL) and carbon disulphide (11.7 mL, 0.15 mole) and triethylamine (15.45 g., 0.15 mole) stirred mechanically at 0 0 C to get triethylammonium dithiocarbamate salt.The salt was then filtered, washed with dry ether, dried and crystallized from chloroform to get dithiocarbamate salts.Further the mixture of triethylammonium N-(2-methylphenyl) dithiocarbamate (0.05 mole) and anthranilic acid (7.2g., 0.05 mole)in ethanol (25 mL) was refluxed on a steam bath for 6 h, cooled and the separated solid was filtered and washed with water and further dissolved in 10% ethanolic sodium hydroxide solution, filtered and reprecipitated by the addition of dilute hydrochloric acid.The product obtained was filtered, washed with water and recrystallized from ethanol to give Ia.Yield: 89%, M.P.291 o C., Mol.Formula : C 15 H 12 N
IV b-3 1720(cyclic amido), 1680(acyclic >C=O), 1620(>C=N).activity was studied, it was found that the 3-methylphenyl, 4-methyl-phenyl,3-chloro-phenyl and 4-chlorophenyl quinazolinone derivatives condensed with 4-bromobenzaldehyde are expected to exhibit spectacular anti-tuberculosic activity.Whereas, other derivatives are also expected to exhibit good anti-tuberculosic activity.Hence these compounds are recommended for the screening of anti-tuberculosic activity .QSAR study of the compounds was similarly done for the anti-mycobacerial activities.It was found that 3-methylphenyl, 4-methyl-phenyl and 4-chloro-phenyl quinazolinone derivatives condensed with 4-bromobenzaldehyde are expected to exhibit spectacular antimycobacterial activity.Whereas, other derivatives are also expected to exhibit good antimycobacterial activity.Hence these compounds were recommended for the screening of antimycobacterial activity too.
Similarly the derivatives of quinazolinones condensed with different aromatic ketones were when subjected to PASS, we found only one activity at Pa>70%.The derivatives with R 1 =2-Me are expected to exhibit spectacular HDL cholesterol increasing activity.Whereas the derivatives of quinazolinones condensed with unsubstituted benzophenone were found to be more probably active as compared with those with substituted ones.In fact the quinazolinones condensed with different aromatic ketones are expected to be exhibit more HDL cholesterol activity as compared to those with aldehydes.

Table 1 .
General characteristics and elemental analysis data of the compounds I (a-g)

Table 5 .
General characteristics and elemental analysis data of the compounds IV (a-g)(1-3)

Table 7 .
General characteristics and elemental analysis data of the compounds V (a-c)(1-4)

Table 8 .
General characteristics and elemental analysis data of the compounds V (d,e)(1-4)

Table 9 .
General characteristics and elemental analysis data of the compounds V (f,g)(1-4)