SYNTHESIS, CHARACTERIZATION AND BIOASSAY OF SOME NOVEL 6,8-DIOXYGENATED-7-SUBSTITUTED ISOCOUMARINS, DIHYDROISOCOUMARINS AND RELATED COMPOUNDS

Abstract

The work presented in this thesis has been divided into two parts. Part one deals with the synthesis, characterization and biological activity of some 7-substituted 6,8- dioxygenated isocoumarins and 3,4-dihydroisocoumarins. Chapter one includes general introduction, nomenclature, structural types, biosynthesis, and extensive examples on pharmacological efficacy of isocoumarins and 3,4-dihydroisocoumarins from literature. It also provides some of the most significant synthetic routes and the reactions of isocoumarins and 3,4-dihydroisocoumarins and their interconversion. The total synthesis of structural analogues of some naturally occurring bioactive isocoumarins and dihydroisocoumarins viz. Hiburipyranone, Cytogenin, Montroumarin, Scorzocreticin, Annulatomarin, Thunberginol B, starting from 3,5-dimethoxy-4-methyl homophthalic acid is the subject of Chapter two. The synthesis of 3,5-dimethoxy-4- methylhomophthalic acid from simplest precursor p-toluic acid was carried out. The substituted homophthalic acid was then converted into corresponding anhydride which was then condensed with various acyl and aroyl chlorides to afford the corresponding 3- alkyl or 3-arylisocoumarins. The isocoumarins were then converted into corresponding 3,4-dihydroisocoumarins and the latter were then demethylated to afford corresponding 6,8-dihydroxy-3,4-dihydroisocoumarins. The structures of all of the synthesized compounds were confirmed using FTIR, 1H NMR, 13 C NMR and mass spectral data. Chapter three provides the physical constants and spectroscopic data of the synthesized compounds. Chapter four deals with the biological activities of the compounds synthesized. Antibacterial activity was determined against ten different Gram positive and Gram negative bacterial strains (Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Lactobacillus bulgaricus, Escherichia coli, Klebsiella pneumonae, Pasteurella multocida, Proteus vulgaris, Pseudomonas aeruginosa and Salmonella typhi) using agar well diffusion method. In vitro antimalarial activity was performed against malarial parasite Plasmodium falciparum. The cytotoxic activity of the synthesized compounds was determined against human keratinocyte cell lines. Chapter five depicts total synthesis of a natural product 8-hydroxy-7- hydoxymethyl-6-methoxy-3,4-dihydroisocoumarin (Stellatin) isolated from mycelium of Aspergillus variecolor. The structures of the precursor compounds and the Stellatin were determined by FTIR, NMR and mass spectroscopic data. These compounds were evaluated for their antibacterial activity against ten different gram positive and gram negative bacterial strains. The cytotoxic activity was performed against human keratinocyte cell lines. Part two is related to the synthesis of some 3-(substituted phenyl)isocoumarins, 3- (substituted phenyl)isocoumarin-1-thiones, 3-(substituted phenyl)isoquinolones and some 1-aryl-7,8-dichloroisochromans. Chapter seven, after general introduction, describes the synthesis and biological activity of these compounds. The unsubstituted homophthalic acid was converted into anhydride by treatment with acetic anhydride. The latter was then converted into 3-(substituted phenyl)isocoumarins by reacting it with suitable acid chlorides. The isocoumarins were then converted into corresponding 3-(substituted phenyl)isoquinolones by treatment with formamide. The 3-(substituted phenyl) isocoumarin-1-thiones were synthesized from isocoumarins using Lawesson’s reagent under microwave irradiation. Microwave assisted synthesis of some (±)-1-aryl-7,8- dichloroisochromans was carried out by condensation of 2-(3,4-dimethoxyphenyl) ethanol with a variety of aromatic aldehydes via an acid catalyzed oxa-Pictet-Spengler reaction. All of these synthesized compounds were characterized by IR, 1H, 13C NMR and mass spectroscopic data. In vitro antibacterial activity of these compounds was determined against ten different Gram positive and Gram negative bacterial strains using agar well diffusion method. The comparative analysis of the antibacterial activity of the 3-(substituted phenyl)isocoumarins, 3-(substituted phenyl)isocoumarin-1-thiones and 3-(substituted phenyl)isoquinolones is described. Accordingly, the antibacterial activity increases when isocoumarins were converted into corresponding isocoumarin-1-thiones but decreases on conversion into corresponding isoquinolones.