MICROWAVE ASSISTED SYNTHESIS & QSAR STUDY OF SOME NOVEL PYRAZOLYL THIAZINE DERIVATIVES

MICROWAVE ASSISTED SYNTHESIS & QSAR STUDY OF SOME NOVEL PYRAZOLYL THIAZINE DERIVATIVES

1. S. Kapase, S. S. Khot, S. A. Kenawade and S. R. Dhongade*

Research Laboratory in Heterocyclic Chemistry, Devchand College, Arjunnagar, Maharastra India

ABSTRACT: This work involves synthesis of pyrazolyl thiazine derivatives from different chalcones [1(a-b)] synthesized from substituted   acetophenones and different aromatic aldehydes in basic medium by Claisen-Schmidt reaction. These chalcones [1(a-b)] on condensation with different hydrazides [2(a-b)] and isothiocyanates [3(a-b)] when irradiated with microwaves (20%, 140watts) in scientific microwave oven, give different 2-phenyl-2,5-dihydro-pyrazole-1-carbothioic acid phenyl amide derivatives [4(a-g)] which on further MW assisted condensation with substituted acetophenones and different aromatic aldehydes, furnish pyrazolyl thiazine derivatives [7(a-j)]. Library of such pyrazolyl thiazine derivatives has been generated and the structures were subjected to PASS for their probabilities of being active biologically. QSAR study of the library was done to find out most active Molecules.

Pyrazolyl thiazine, Substituted acetophenone, Substituted aromatic   aldehydes, Hydrazides, Substituted isothicynates, MW assisted condensation

INTRODUCTION: Thiazine is a six membered heterocyclic ring which contains two hetero atoms (N and S) placed   at the 1, 3 or 1, 4 positions. 1, 3 Thiazines are very useful units in the field of medicinal and pharmaceutical chemistry and have been reported to exhibit variety of biological activities ¹. A large group of dyes has phenothiazine structure including methylene blue. Thiazines are used in dyes, tranquilizers and insecticides. Thiazine is fairly basic diuretic supplement which reduces water and increases vascularity, so it is also used as anabolic agent in medicine ². The 1, 3-thiazine nucleus is active core of cephalosporin which is among the widely used β-lactum antibiotics.

The ability of thiazine to exhibit antitubercular, antibacterial, anti-HIV and cannabinoid receptor agonist has been reported ³. Sawant et al synthesized 1, 3-thiazines and carried out antimicrobial screening which revealed that the compounds with methoxy substituent were found better antimicrobial agents ⁴. The potential use of chlorpromazine derivatives of this phenothiazine as an antimicrobial, increasing activity of antibiotics to which bacteria are susceptible and reverse resistance of Staphylococcus aureus and Corynebacteria topenicillin strongly supports that phenothiazine can be exploited for the management of bacterial infections ⁵.

Whereas, chalcones undergo a variety of chemical reactions and are found useful in synthesis of variety of hetero cyclic compounds like pyrimidine and thiazole derivatives which are synthesized through the reaction of chalcones with urea and thiourea in the presence of alkaline media in refluxing ethanol ⁶. F. K. Mohammed et al synthesized new chromene base heterocyclic thiazine from 2-amino-5-hydroxy-4-phenyl-7-methyl-4H[1-chromeno-3-carbonitrile; which showed a good biological activity ⁷. The derivatives of 1,3 thiazines having       N-C-S linkage have been used as antitubercular, antibacterial, antimicrobial, antitumor, insecticidal, fungicidal, herbicidal agents, in tranquilizers and various dyes etc.^8-16. Further, 1, 3-thiazine core moieties have remarkable potential as anti radiation agents. 1,3-Thiazines are used in various organic synthesis and transformations as reaction intermediates^8-16. In light of these biological activities it appeared of interest to synthesize 1, 3 thiazine derivatives.

However,   synthesis of very few pyrazolyl thiazine derivatives like 2- [2- [3 -(2-amino – 4 - chloro-phenyl)- 4 - formyl – pyrazol – 1 - yl] – 6 - (4-chloro-phenyl)-6H-[1, 3] thiazin – 4 - yl] -N-phenyl-acetamide, 2 -{6-(4-chloro-phenyl) – 2 - [4-formyl-3- (4-nitro-phenyl)-pyrazol-1-yl] - 6H -[1,3] thiazin-4-yl}- N- phenyl- acetamide, 2-[2-[3-(4-amino-phenyl) - 4 - formyl-pyrazol -1 -yl]-6-(4-chloro-phenyl)-6 H-[1, 3]thiazin-4-yl] - N - phenyl-acetamide, 2 - {6-(4-chloro-phenyl)-2-[4-formyl-3-(2-hydroxy-phenyl)-pyrazol-1-yl]- 6H-[1,3]thiazin-4-yl}-N-phenyl-acetamide have been reported.¹⁷

PASS:

PASS is a software application that predicts 565 possible biological activities of a user selected (set of) compound(s). These activities include 5-hydroxytryptamine antagonists, neuromuscular blocking agents, antibiotics, antidepressants, antiviral agents (AIDS), contraceptives, tumor necrosis factor antagonists and many others. Using PASS predictions, novel pharmaceutical agents have been discovered with anxiolytic, anti-inflammatory, antihypertensive, anticancer and other activities. PASS is applicable to chemical libraries containing millions of compounds.

The biological activities of chemical compounds are related to their physicochemical properties by some functions as shown in equation (1).

Biological activity = f (physicochemical properties)…….. (1)

Thus, "the biological activity spectrum" is defined as the "intrinsic" property of a compound depending only on its structure and physico-chemical characteristics. Prediction of this spectrum by PASS is based on SAR analysis of the training set containing thousands of compounds which have many kinds of biological activities. .In PASS biological activities are described qualitatively (“active” or “inactive”).^18-21

 Importance of PASS:

Experimental determination of biological activity of a drug is time and cost consuming procedure, so making the use of PASS is generally important.

PASS can be effectively used for finding of compounds with required properties and without undesirable side effects.

It used for selecting the most prospective compounds from the set of available samples for specific screening. For determining of more relevant screens for particular compound.

Due to this significance of PASS, it is used in the present study as a tool to design the drug with highest probable activity.

FIG.1:

MATERIALS AND METHOD:

Melting points were determined with Melting point apparatus using open capillary tubes and are uncorrected. The IR spectra were recorded in KBr pellets on a Nicolet 400D spectrometer and ¹H NMR spectra were recorded in CDCl₃ with TMS as internal standard on a Bruker spectrometer at 400 MHz. Mass spectra were recorded on a Shimadzu GCMS-QP 1000 EX mass spectrometer at 70 eV. Purity of the compounds was checked by TLC on silica- G plates of 2 mm thickness using n-hexane and ethyl acetate as solvent system. The visualization of spot was carried out in an iodine chamber. Biological activities are predicted by using computer programme PASS.

Synthesis of (E)-3-(4-ethoxy-phenyl)-1-(4-methoxy-phenyl)-propenone [1-a]:

4-Methoxyacetophenone 1.50 g, (0.01 M) and 4-ethoxybenzeldehyde 2.82 g (0.01 M) were mixed in ethanol (25 mL) in 100 mL RBF. 40% NaOH solution (3mL) was added and the reaction mixture was irradiated with microwaves at 20% microwave power (140 W) for 3 mins. The reaction mixture was cooled and neutralized with 2N HCl (2-3 mL) to obtain the product. The separated product was filtered, washed with ethanol (5 mL) and recrystallized from ethanol to get Yield 2.56 g (86%)of [1-a] (see Figure 1)

76. Formula: C₁₈H₁₈O_3, M. Wt: 282, M.P.116⁰C, Elemental analysis: C, 76.61(76.67%); H, 6.47(6.49%); O, 17.01(17.05%). IR (KBr) ν _max, 1040(C-O), 1209(O-CH₃), 1410(CH=CH), 1515(C-C), 1670(C=O), 3019(Ar-CH). H¹NMR(CDCl₃):