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Title: Synthesis and Biological Evaluation of Novel 2,1-Benzothiazine Derivatives
Authors: Ahmad, Shakeel
Keywords: Physical Sciences
Issue Date: 2020
Publisher: Government College University, Faisalabad
Abstract: 2,1-Benzothiazine ring system is famous for its excellent biological activities. In this research work, a variety of the novel derivatives of 2,1-benzothiazine 2,2-dioxide are synthesized. The precursor, 2,1-benzothiazine 2,2-dioxide was primarily prepared by previously reported method with slight modifications in the methodology (Scheme-1) which resulted in improved yields. The carbonyl group at position 4 on thiazine ring was converted into hydrazone by monohydrated hydrazine and the resulted products were further reacted with substituted aromatic aldehydes/ketones, 2-furaldehyde, 2-formylpyridine and cyclopentane carbaldehyde to obtain the Schiff bases (di-immine) derivatives of 2,1-benzothiazine-2,2-dioxide. All conjugates 100a-m, 101a-f & 102a-c were characterized by 1H NMR, 13C NMR, mass spectrometry and crystal structure elucidation. In this series, the best potent inhibitor compound against monoamine oxidase A is 100i, while excellent inhibitory activity towards monoamine oxidase B by 101d was prepared by using a variety of the N-benzyl substituted moieties. The compounds 100h, 100c, 100f, 100a, 100j and 100k were further evaluated for the potential monoamine oxidase inhibition activity A and B, where most of the compounds 100m, 100g, 100j and 102b were found to be highly active against monoamine oxidase A. Majority of the synthesized compounds were identified as a potent and selective for monoamine oxidase B. In-addition, the synthesized novel series of pyranobenzothiazines i.e., 106a-r & 107a-r, were evaluated for monoamine oxidase (MAO) inhibition activity, where the compounds 106j, 107l & 107r demonstrated potent activity against MAO-A and compounds 106g, 106h, 107i & 107q found to be most active against MAO-B. Moreover, the compound 107n exhibited excellent dual inhibition against MAO-A and MAO-B as well as the anti-diabetic activity (α-glucosidase inhibition) resulted that synthesized novel conjugates 107a-n and 107(p-r) are assayed for their α-glucosidase inhibition potential. However the most of the compounds are exhibited good activity but selective compounds 106n and 107g containing (IC50 = 4.80 and 4.69 μM), is analyzed to be excellent inhibitory activity against α-glucosidase enzyme, While the quinoline substituted pyranobenzothiazine derivatives were also synthesized using 3-formylquinolines as aldehydes i.e., 2-amino-6-benzyl-4-(2-substituted-5-methylquinolin-3-yl)-4,6- dihydrobenzo[c]pyrano[2,3-e][1,2] thiazine-3-carbonitrile 5,5-dioxide 108a-b and 1-benzyl-3- ((1-benzyl-4-hydroxy-2,2-dioxido-1H-benzo[c][1,2]thiazin-3-yl)(X-substituted phenyl) methyl)- 1H-benzo[c][1,2]thiazin-4-olate 2,2-dioxide 111a-j or (bis adduct) were prepared by adopting Knovenagal condensation reaction (MCRs). Furthermore acidic hydrogens present at three position of thiazine ring were replaced by methyl 2-chloroacetate. Finally, it was converted to cyclic 6-benzyl-3-hydroxy-4a, 6-dihydro-4H-benzo[c]pyridazino[3,4-e][1,2]thiazine 5,5-dioxide 115 after treating with monohydrated hydrazine. Variety of amides were also used to react with 2,1-benzothiazine 2,2-dioxide precursor to resulted 2-(1-benzyl-2,2-dioxido-4-oxo-3,4-dihydro1H-benzo[c][1,2]thiazin-3-yl)-N-(x-substituted phenyl) propanamide 117a-e. The structures were elucidated by various spectroscopic techniques such as 1H NMR, 13C NMR, mass spectrometry and crystal structure elucidation. Molecular ion peaks were also observed in all cases by EIMS. Out of the synthesized novel series, lots of the important compounds were recrystallized in suitable solvents and characterized by CCD diffractometer and crystal structure elucidation. Furthermore stereochemistry of some of the synthesized compounds was also discussed briefly.
Gov't Doc #: 20957
Appears in Collections:PhD Thesis of All Public / Private Sector Universities / DAIs.

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