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Title of Thesis

Muhammad Tahir Hussain
Institute/University/Department Details
Department of Chemistry/ Quaid-i-Azam University, Islamabad
Number of Pages
Keywords (Extracted from title, table of contents and abstract of thesis)
isocoumarins, 3-4-dihydroisocoumarins, nitrogen, sulphur selenuim, tellrium, homalicine, homalium zeylanicum, hiburipyranone, xyridine, hydrangenol, herbicide, insecticide, plant disease

The work presented in this thesis consists of synthesis, characterization and biological screening of some Isocoumarins, Dihydroisocoumarins and related compounds. The thesis is divided into four chapters.

Chapter one, after the general introduction, nomenclature, structural types, biosynthesis etc., provides extensive examples on biological activities of isocoumarins and dihydroisocoumarins from literature. Some of the most important methods of syntheses and reactions of isocoumarins and dihydroisocoumarins has also been summarized along with the methods of their inter conversion.

The multistep synthesis of some naturally occurring isocoumarins and dihydroisocoumarins starting from homophthalic acid has been described in chapter two which also includes synthesis of models of some natural products. Thus, total synthesis of naturally occurring homalicine and (-)-dihydrohomalicine, isolated (1975) from the roots of Homalium zeylanicum is described, which is a first total synthesis of any naturally occurring glucoside of isocoumarin and dihydroisocoumarin. Key step of this synthesis is the coupling of glucose with 3-(3-hydroxyphenyl) isocoumarin and (dl)-3-(3-hydroxyphenyl)-3,4-dihydroisocownarin, which was successfully completed. One step synthesis of naturally occurring 3-propylisocoumarin, isolated (1976) from the roots of Felicia wrightii is described. A convenient synthesis of (dl)-3-propyl-3,4-dihydroisocoumarin, (dl)-3-( 4' -hydroxyphenyl)-3,4-dihydroisocownarin, (dl)-3-(3',4 'dimethoxyphenyl)- 3, 4-dihydroisocoumarin,(dl)- 3-(3',4',5' -trimethoxypheny 1)-3,4-dihydroisocoumarin and 3-(3',4'-dihydroxyphenyl)isocoumarin was also carried out. These compounds act as models of hiburipyranone, hydrangenol, phyllodulcin, macrophylloside A and 8-hydroxy-3-(3',4'-dihydroxyphenyl) isocoumarin respectively. 3-(4-Hydroxyphenyl)-3,4-dihydroisocownarin acts also as a model for Hydrangenol-8-β-D-glucoside. Partial synthesis of feralolide, isolated (1993) from commercial sample of Cape aloe, a natural drug well known for its cathartic properties and bittering agent in alcoholic beverages, has been carried out by classical method starting from the key intermediate 3,S-dimethoxyphenylacetic acid. Coupling of 3,5-dimethoxyphenylacetyl chloride with 3,5-dimethoxybenzylmagnesiurn bromide (Grignard's reagent) afforded a ketone, which on reduction, acetylation and Vilsmeier Haak formylation yielded (dl)-1,3di-(2'-formyl-3',S'-dimethoxyphenyl)propan-2-yl acetate. Further steps are given in Scheme-2.l9.

Third chapter deals with the synthesis of some non-natural isocoumarins and (dl)-3,4-dihydroisocournarins. These compounds were prepared in order to check their anti-microbial, serine proteases inhibition, herbicidal, insecticidal and plant disease control activities. This includes the synthesis of 3-(fluorophenyl) isocoumarins, 3-(bromophenyl)isocoumarins, 3-(iodophenyl) isocoumarins, 3-methyisocoumarin, 3-(2',3',4'-trimethylphenyl)isocoumarin and isocoumarin derivatives of ibuprofen, flurbiprofen, naproxen, valproic acid and I-naphthoic acid. All these isocoumarins were converted to their (dl)-dihydro-derivatives except the isocoumarins of ibuprofen, flurbiprofen and naproxen. The (dl)-dihydro-derivatives were prepared by converting the respective isocoumarins to keto-acids by basic hydrolysis and hydroxy-acids by reduction of keto-acids with sodium borohydride followed by cyclodehydration using acetic anhydride.

Results of anti-fungal, anti-bacterial, serine proteases inhibition, herbicide, insecticide, plant disease control screens of synthesized compounds are summarized in fourth chapter. Thirty eight isocoumarins, dihydroisocoumarins and related compounds were tested for their activity against various fungi. 2-(3'-Bromobenzoylmethyl)benzoic acid is found to be most active (71.4% inhibition) against Pseudallescheria baydii. Compounds having halogen atoms have been found to be more active than those which possess alkyl substituents. Thirty six selected compounds were tested for their antibacterial studies against various strains of gram-positive and gram-negative bacteria.

Their activity was found to be lower than the standard drugs. Chymotrypsin inhibitary assay was carried out for thirty five compounds out of which thirteen compounds have shown more than 50% inhibition. Six compounds were tested for serine proteases inhibition studies. Maximum inhibition (12%) was shown by 3-(3-Iodophenyl) isocoumarin against porcine pancreatic elastase (PPE). Four representative isocoumarins and dihydroisocoumarins were tested for activity against five different types of herbs. "Arabidopsis" was controlled >35% by 3-(4-fluorophenyl)-3,4-dihydroisocoumarin. Results of insecticidal screens show that insets (TSSM, TBW & BBA) were controlled >75%. Potato late blight (PLB) was controlled >55% by 3-(4-fluorophen yl)- 3 ,4-dihydroisocoumarin.

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S. No. Chapter Title of the Chapters Page Size (KB)
1 0 Contents
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2 1 Introduction 1
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  1.1 Nomenculature and structural Types 2
  1.2 Physical Properties 4
  1.3 Nitrogen, Sulphur Selenuim and Tellrium Analogues 4
  1.4 Applications and Biological Activity 6
  1.5 Behaviour towards Human Beings 14
  1.6 Biosynthesis 15
  1.7 Synthesis of Isocoumarins and 3 ,4 -Dihudroisocoumarins 20
  1.8 Reactions of Isocoumarins and 3 ,4 -Dihydroisocoumarins 33
  1.9 Interconversion of Isocoumarins and 3 ,4 -Dihydroisocoumarins 36
  1.10 Plan of work 38
3 2 Synthesis of Naturally Occurring Isocoumarins and 3 ,4 -Dihydroisocoumarins 41
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  2.1 Synthesis of Homalicine and (dl )- 3,4-Dihydroisocoumarins of Homalium Zeylanicum 41
  2.2 One Step Synthesis of Naturally Occurring 3-Propylisocoumarin and its Conversion to 3-Proyl-3,4-Dihydroisocoumarins which also act as Models of Xyridine A and Hiburipyranone Respectively 63
  2.3 Synthesis of Models of Hydrangenol, Hydrangenol-8-β-D-glucodie, Phyllodulcin, Macrophylloside A and 8-Hydroxy-3-(3; ,4 -Dihydroxyphenyl) isocoumarin 79
  2.4 Partial Synthesis of Feralolide of Cape aloe 102
4 3 Synthesis of Non-Natural Isocoumarins and 3 ,4 -Dihydroisocoumarins) 117
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  3.1 Synthesis of some New 3-(Fluorophenyl) Isocoumarins and their conversion to (dl)-3 ,4 -Dihdrosicoumarins 117
  3.2 Synthesis of some New 3-(Bromophenyl) Isocoumarins Their conversion to (dl)-3 ,4 -Dihdrosicoumarins 132
  3.3 Synthesis of some New 3-(Iodophenyl)) Isocoumarins Their conversion to (dl)-3 ,4 -Dihdrosicoumarins 147
  3.4 Synthesis and Characterization of Isocoumarins Derivatives of Ibuprofen, Flurbinprofen, Naproxen, Valproic acid and 1-Naphthoic acid and Conversion of latter two into (dl)-3 ,4 -Dihydroisocoumarins 162
  3.5 Synthesis of 3-Methylisocoumarins and 3-(2’ ,3’,4 -Dihydroisocoumarins 162
5 4 Biological activity of the synthesized Isocoumarins 3 ,4 -Dihydrosocoumarins and Related compounds 204
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  4.1 Anti-fungal Studies 204
  4.2 Anti-bacterial studies 215
  4.3 Chymotropism Inhibitory Assay 219
  4.4 Serine proteases Inhibition studies 221
  4.5 Herbicide screen 224
  4.6 Insecticide screen 225
  4.7 Plant disease control screen 227
6 5 References 229
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