Synthesis and QSAR Study of (4-Oxo-3-aryl-3,4-dihydro-quinazolin-2-ylsulfanyl)-propionic Acid arylidene/aryl-ethylidene-hydrazides via Microwave Assisted Solvent Free Reations

http://www.e-journal.net ISSN: 0973-4945; CODEN ECJHAO E-Journal of Chemistry Vol. 1, No. 2, pp 115-126, April 2004 Synthesis and QSAR Study of (4-Oxo-3-aryl-3,4dihydro-quinazolin-2-ylsulfanyl)-propionic Acid arylidene/aryl-ethylidene-hydrazides via Microwave Assisted Solvent Free Reations M. B. DESHMUKH*and SAVITA DHONGADE (DESAI) Department of Chemistry, Shivaji University, Kolhapur, 416004 (India) Received 8 March 2004; Accepted 23 March 2004 Abstract: In the present work, s-alkylated derivatives of thio-quinazolinone were obtained using Methyl 2-chloro propionate via a solvent-free microwaveassisted 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) 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 antituberculosic, anti-mycobacterial & HDL cholesterol increasing activities. Keywords: Quinazolinone, Antituberculosic, Anti-mycobacterial, HDL cholesterol increasing, QSAR 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 reactions1. The use of domestic microwave oven in this regard is now a well-established procedure in MORE2 (microwave induced organic reaction enhancement) chemistry. It has been reported that the rate of variety of organic reactions such as Diels-Alder3, ene4, Claisen reaction5, oxidation6, reduction7, diacetylation8, deacetylation9, deoximation10, esterification11, hydrolysis of ester12, Doebner condensation13, 14 Knoevenagel condensation could 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 derivatives15-17. 116 M. B. DESHMUKH et al. Quinazoline derivatives are of special importance because of their versatile biological & pharmacological activities18-20, especially anti-inflammatory21-23, anti-convulsant24, hypnotic25, anthemintic26, hypotensive27, antibacterial28 agents etc. In the present work, s-alkylated derivatives of thio-quinazolinone were obtained using Methyl 2-chloro propionate 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) 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 Section All mps.were determined in open capillary tubes and are uncorrected. IR spectra were recorded in KBr on Shimadzu IR-437 spectrophotometer and PMR spectra in CDCl3 and DMSO-d6 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-(4-Oxo-3-o-tolyl-3,4-dihydro-quinazolin-2-ylsulfanyl)- propionic acid methyl ester (II-a) The mixture of Compound I-a 0.67 g (2.5 mmol), methyl 2-chloropropionate 0.306 g (2.5mmol) in of DMF (5 mL) to which powdered NaOH (0.5 g) was smoothly mixed and placed inside a Pyrex-glass open vessel .The mixture was irradiated with microwaves (900 W /2450 MHz frequency) for the specified time on 50% power using a domestic microwave oven ‘ Sharp R-758B’. When the irradiation was stopped, the final temperature was measured by introducing a glass thermometer into the homogenized reaction mixture. To this mixture then 2N HCl (10 mL) was added and the separated solid was filtered, conveniently dried and recrystallized from aq. Ethanol to get 0.761 g of II-a. Yield 86%, M.P.145 oC, Mol. Wt.354, Molecular formula C19H18N2O3S, Elemental analysis C, 64.5 (64.41%); H, 5.0 (5.08%); N, 7.8 (7.91%). IR(KBr): νmax, 1755(C=O),1710(cyclicC=O), 1620(C=N), 1060cm-1(-O-), PMR (DMSO-d6): δ, 1.4(3H,d J=7Hz. ,CH3),2.35(3H,s,Ar-CH3), 3.75(3H, s,OCH3), 4.3(2H,q J=7Hz.,CH), 7.2-8.2(8H,m,Ar-H) ppm. Similarly, the other compounds II-(b-g) were prepared and their purity was checked by TLC and the structures confirmed on the basis of IR and PMR spectral and elemental analysis data. 2-(4-Oxo-3-o-tolyl-3,4-dihydro-quinazolin-2-ylsulfanyl)-propionic acid hydrazide (III-a) Compound II-a 3.54 g (0.1mol) mixed with 0.1 mols of hydrazine hydrate in methanol 5 mL was refluxed on a steam bath for three hours. The separated solid was filtered and recrystalized from ethanol to get 3.115 g of III-a. Yield 88%, M. P. 188oC. , Molar Mass: 354,Mol. Formula: C18H18N4O2S, Elemental Analysis: C, 60.9(61.00)%); H, 5.1(5.12%); N, 15.8 (15.81%), IR (KBr): νmax, 3200-3080(NHNH2), 1680(cyclic >C=O), 1660(acyclic>C=O), 1620cm-1(C=N), PMR(DMSO-d6):δ, 1.55 (3H,d,J=7.5Hz.,CH3),3.75 (3H, s, Ar-CH3),4.5(1H, q, J=8.5Hz, CH),-4.8(2H, s, br, exchangeable with D2O, NH2), 6.88.1(8H,m,Ar-H), 9.45(1H, s, CONH) ppm. Synthesis and QSAR Study 117 2-(4-Oxo-3-o-tolyl-3,4-dihydro-quinazolin-2-ylsulfanyl)-propionic acid(4-methoxybenzyledene)-hydrazide ( IV-a4) Mixture of Compound III-a 3.54 g (0.1 mol) and 4-methoxy benzaldehyde 1.36 g (0.1 mol) in DMF (5 mL) to which 2-3 drops of acetic acid were added and the reaction mixture was mixed well and placed inside a Pyrex-glass Erlenmeyer flask loosely corked with cotton. The mixture was irradiated with microwaves (900 W /2450 MHz frequency) for 5 minutes on 50% power using a domestic microwave oven‘Sharp R-758B’. When the irradiation was stopped, the mixture was added to ice-water mixture and the separated solid was filtered, conveniently dried and recrystallized from aq. ethanol to get 3.68 g of IV-a4. Yield 78%, M.P. 332oC., Molar Mass: 472, Mol.Formula : C26H24N4O3S, Elemental analysis: C,66.1(66.08%); H,5.1(5.12%); N,11.8(11.86 %) ,IR (KBr): νmax, 1720(cyclic amido >C=O), 1680(acyclic >C=O), 1610 cm-1.(C=N), PMR(DMSO-d6): δ,1.55(3H,d, J=7.5Hz.,CH3), 2.9(3H,s,Ar-CH3), 3.8(3H,s, Ar-OCH3), 4.5(1H,q, J=7.5Hz.,CH),7.38.3(12H,m,Ar-H), 8.5(3H,s,=C-CH),9.6(1H,s,CONH) ppm. SCHEME O a, R=2 M e b, R = 3 M e c, R = 4 M e d, R=3 C l e, R = 4 C l f, R = 3 O C H 3 g, R=4 O C H 3 R N N S H [I (a -g )] C lC H C H 3C O O M e DMF NaOH O R N N S (...truncated)