Synthesis, Characterization and Biological Assay of Some Novel Coumarinyl Heterocycles and Study of Halogen Bonding in N-Heterocyclic Organic Salts

Aliya Ibrar, . (2015) Synthesis, Characterization and Biological Assay of Some Novel Coumarinyl Heterocycles and Study of Halogen Bonding in N-Heterocyclic Organic Salts. Doctoral thesis, Quaid-i-Azam University, Islamabad.

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Abstract

I) Pharmacological evaluation and docking studies of some new 3-(5(arylamino)-1,3,4-thiadiazol-2-yl)-2H-chromen-2-one and 3-(4-aryl-5-thioxo-4,5dihydro-1H-1,2,4-triazol-3-yl)-2H-chromen-2-one derivatives as cholinesterase inhibitors This work reports the synthesis of 1,2,4-triazole 96(a-g) and 1,3,4-thiadiazole 97(a-g) derivatives linked to a biologically potent coumarin nucleus. The synthesized series of compounds were evaluated as potential inhibitors of cholinesterases. The molecular docking studies of the prepared compounds have also been reported which revealed the competitive binding mode of inhibitors for the AChE and BChE enzymes. We hope these results can be useful for future efforts to synthesize and evaluate coumarin derivatives in order to enhance their anti-cholinesterase properties and selectivity.</br> Synthesis, biological evaluation and molecular modeling of novel coumarinyl oxadiazole derivatives as cholinesterase and aldose reductase inhibitors In this study, a new series of coumariny oxadiazole derivatives 100(a-h) were synthesized and screened against cholinesterases. Most of the compounds showed inhibitory activity against acetylcholinesterase and butyrylcholinesterase. Among the tested compounds, 100a was found to be the most potent compound against acetylcholinesterase with IC50 of 6.07 ± 0.23 ?M whereas 100e emerged as a lead candidate against butyrylcholinesterase with IC50 value of 0.15 ± 0.09 ?M. The synthesized compounds were also tested against aldose reductase (ALRI and ALR2)where 100b was emerged as the most potent with IC50 of 3.36 ± 1.34 µM against ALR1 and 100d was more potent towards ALR2 with IC50 of 0.31 ± 0.002 µM. Molecular docking studies were also performed to predict the binding modes of the most active inhibitor against cholinesterases.</br> Design, synthesis and biological evaluation of coumarinyl thiazole derivatives as aldose reductase inhibitors Novel coumarinyl thiazole derivatives were synthesized in a one-pot three component cascade process and their activity against ALR1 and ALR2 as potent inhibitors was determined. Valproic acid and sulindac were used as standard inhibitors with IC50 values of 57.4 and 0.293 µM for ALR1 and ALR2, respectively. Compounds 104m and 104e were most potent towards ALR1 and ALR2, respectively. Results obtained through our analysis show that derivatives of coumarinyl thiazoles may be considered as selective and potent inhibitors of ALR1 and ALR2 to control effectively the diabetic complications. </br> Design, synthesis and biological evaluation of (E)-N'-(3-(substituted)-4-(2oxo-2H-chromen-3-yl)thiazol-2(3H)-ylidene)-2-oxo-2H-chromene-3carbohydrazide derivatives This work is towards the synthesis of a series of coumarinyl iminothiazole derivatives 105(a-j) which has been prepared by the reaction of bromoacetyl coumarin and thiosemicarbazides. The structural diversity of the synthesized derivatives was ensured by using a diverse range of substituents including electron-donating and electron-withdrawing groups on aryl part of thiosemicarbazides. The synthesized analogues were screened against alkaline phosphatase. Among the tested compounds, 105j emerged as a potent inhibitor with IC50 value of 1.11 ± 0.6 ?M. The synthesized compounds were also assayed for their anti-leishmanial potential and compound 105i was found to be the lead candidate with 70.4 ± 2.2% inhibition at 100 ?M. The prepared compounds also showed cytotoxic behavior against kidney fibroblast (BHK21) and lung carcinoma (H-157) cell lines. Most active compound was 105l which showed highest inhibition of 66.8 ± 1.1 and 65.0 ± 1.8% against BHK-21 and H-157 cell lines, respectively. </br> Design, synthesis and biological evaluation of coumarinyl triazolothiadiazine derivatives A series of coumarinyl linked hybrid structures like triazolothiadiazines 108(a-j) were synthesized by the cyclocondensation reaction of 4-amino-1,2,4-triazole bearing coumarinyl motif and bromoacetophenones in absolute ethanol under reflux. The prepared compounds were evaluated against alkaline phosphatase where compound 108j bearing bis-coumarinyl structure at 3- and 6-position of hybrid skeleton turned out to be a potent inhibitor with IC50 value of 1.15 ± 1.0 ?M. The synthesized compounds were also tested against Leismania major and compound 108g with 71.2 ± 1.3% inhibition was found to be the lead member. Cytotoxic activity was also carried out using kidney fibroblast (BHK-21) and lung carcinoma (H-157) cell lines. Compound 108d showed highest cytotoxic potential against H-157 cell lines with 78.2 ± 2.2% inhibition at 100 ?M which is higher than the standard vincristine, used in this assay. Also, compounds 108g and 108e were established as leading derivatives with 69% inhibitions. </br> Investigation of halogen bonding in N-heterocyclic salts Numerous halogen substituted N-heterocyclic salts were synthesized from readily available starting materials by treating with HCl (1.25 M/MeOH), HBr (48% in H2O) and methyl iodide at room temperature and 50 °C, respectively. The synthesized derivatives were confirmed by spectro-analytical techniques including FTIR, 1H and 13C NMR spectroscopy and mass spectrometry. In several cases, the structures were established by X-ray diffraction analysis which confirmed the presence of halogenhalogen interactions in most cases.

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: Synthesis, Characterization,Biological Assay , Coumarinyl, Heterocycles ,Halogen Bonding ,N-Heterocyclic
Subjects: Q Science > QD Chemistry
Depositing User: Bashir khan
Date Deposited: 27 Oct 2017 04:32
Last Modified: 27 Oct 2017 04:32
URI: http://eprints.hec.gov.pk/id/eprint/6930

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