SYNTHESIS OF SOME NEW CHALCONE DERIVATIVES OF PHYSIOLOGICAL IMPORTANCE

Abstract

Heterocyclic molecules are Nature's favourites and are widely encountered in biomolecules. Some of these molecules are essential to life. These molecules play a vital role in the metabolism of living cells. The chemistry of biomolecules has been recognized as a significant field of study. Chalcones is one of the major classes of natural products with widespread distribution in fruits, vegetables, spices, tea, and soya based foodstuff. Chalcone is a generic term given to compounds bearing the l,3-diphenylprop-2-en-l-one framework. They are the first isolable compounds during the course of flavonoid biosynthesis in plants. Chalcones considered as the precursors of flavonoids, isoflavonoids, aurones, catechins, anthocyanidines, and are abundant in edible plants. Chemically these are open chain flavonoids in which the two aromatic rings are joined by a three carbon a,|3-unsaturated carbonyl system. Nature makes them by a combination of shikimic and acetate pathways in a very efficient manner. Chemical elaboration of chalcones can be effected by different substituents in the phenyl rings, by the replacement of the phenyl rings with heterocyclic and polyaromatic rings, by saturation or substitution of the enone linking the two rings, or by cyclisation of the chalcone to give conformationally restricted analogues. Studies have revealed that compounds with chalcone-based structure possess an array of pharmacological activities such as anti-inflammatory, antifungal, antimalarial, anticancer, antibiotic and other activities. The unique structural features of chalcones, the presence of a reactive enone moiety and its relative flexibility compared to other related natural products may predispose the (i) template to interact with diverse receptors and enzymes. The C6-C3-C6 motif is recognised as a "privileged structure" in drug design. The ease with which chalcones are synthesized further enrich the structural diversity of the template through the introduction of features normally associated with ligand-receptor interaction, namely hydrophobic groups, hydrogen bond donor and acceptor features. Because of this the chemistry of chalcones has been a subject of immense curiosity for investigation. The present thesis is aimed to describe the chemistry of chalcones considering their biological importance with emphasis on chemical as well as biological advancement. Fluorescent probe potential of some of the pyrazolines has been explored. Some of the chalcones reported here have been explored for their possible antimicrobial and antimalarial activities. For a systematic presentation, the work presented in the thesis has been divided into the following five chapters. The first chapter is introductory one and deals with general aspects of chalcone, their occurrence in nature, synthetic modification, and plethora of activities shown by them specially in addition and epoxidation processes. Literature reports on chemical as well as biological activities have also been incorporated in this chapter. The second chapter describes the syntheses and characterization of some new chalcones bearing piperazine or 2,5-dichlorothiophene moiety in one of the rings, by normal Claisen-Schmidt reaction with the appropriate benzaldehydes. The structures of chalcones have been established on the basis of elemental analysis and various spectral data. The synthesized compounds have been tested for their antibacterial activity by employing nutrient agar disc diffusion method. The antibacterial activity of chalcones was screened against staphylococcus aureus 209p, E.coli ESS 2231, Proteus vulgaris, K. 0>) pneumoniae and A. fumigatus. The antifungal activity was screened against Candida albicans and Candida albicans ATCC 10231 at concentrations of 250 uM. The standards used were Ciprofloxacin for antibacterial and fluconazole for antifungal activities respectively. All the chalcones were moderate to good active against microbes and activities were found to be comparable to reference drugs. The most potent compound for antibacterial activity was l-(4-(piperazin-l-yl)phenyl)-3-m-tolylprop-2-en-l-one with MIC50 of 3.13 ug/mL against S. aureus, while l-(2,5-dichlorothiophen-3-yl)-3-phenylprop-2-en-l-one showed MIC50 value of 2.22 u.g/mL against Candida albicans. The third chapter deals with the syntheses and antimalarial activity profile of new acridinyl chalcones. Chalcones have been synthesized by nucleophilic substitution of aminochalcones. In the first step, parent chalcones have been synthesized by normal Claisen- Schmidt condensation to give 4'-amino/3'-amino chalcones. The reaction sequence extended by coupling of chalcones with 9-chloroacridine. The scheme for new chalcones can serve as a model for the completetion of the synthetic protocol and to switch to a different synthesis paradigm consecutively. All the newly synthesized chalcones were characterized by C,H,N analysis, UV, IR, 'H-NMR, Mass spectral and HPLC data. Evaluation of the activity of the new acridinyl chalcones against a chloroquineresistant strain of Plasmodiumfalciparum were carried out. Chloroquine was used as the standard reference drug. Investigation on the series of chalcones resulted in inhibition of the maturation of parasite at 10 uM or above concentrations. Particularly one compound, l-(4- (acridin-9-ylamino)phenyl)-3-(4-methoxy phenyl)prop-2-en-l-one showed 71.4% inhibition of parasite at low concentration of 0.4 |ag/mL. Three chalcones were identified with low micromolar (2 uM) inhibiton efficacy against Plasmodium falciparum strain (NF4) in vitro. (HO These inhibitors were found to be inactive when given orally to a Plasmodium yoeliei (strain N-67) infected mice model. Metabolic instability may be responsible for the lack ofactivity in vivo due to possible significant degradation of compounds upon their exposure to a liver microsome preparation. In the fourth chapter, two series of l-thiocarbamoyl-3-(2-naphthyl)-5-(substituted phenyl)-2-pyrazoline and l-(p-toluenesulphonyl)-3-(2-naphthyl)-5-(substitutedphenyl)-2- pyrazoline derivatives were synthesized by a base-catalyzed Claisen-Schmidt condensation of substituted benzaldehyde with 2-acetylnapthalene followed by cyclization with thiosemicarbazide and p-toluenesulphonyl hydrazide respectively. The structures of 2- pyrazolines have been established by C,H,N analysis and UV, IR, 'H-NMR and Mass spectral data. All the 1-/V-substituted pyrazoline derivatives were screened for in vitro antibacterial activity against bacterial strains; Staphylococcus aureus ATCC 29213, Klebsiella Pneumoniae, Escherichia coli ATCC 13607, Proteus vulgaris ATCC 2853, Salmonella. Typhi ATCC 9484 and fungal strains; Candida albicans ATCC 10231 and Candida glabrata ATCC. The MIC values were generally within a range of 3.90-125 ug/mL. Compound \-{ptoluenesulphonyl)- 3-(2'-naphthyl)-5-(4-nitrophenyl )-2-pyrazoline showed the best activity of 3.90 |ag/mL against K Pneumoniae In fifth chapter, a series of N'-nicotinoyl-3-(2-naphthyl)-5-(substituted phenyl)-2- pyrazolines were synthesized by the reaction between isoniazid (INH) and naphthyl chalcones. Structures of these pyrazolines were confirmed by C,H,N analysis, UV, IR, HNMR and Mass spectral data. (iv) Fluorescence studies of the pyrazolines revealed that these compounds have good blue fluorescence. Interaction of these pyrazolines with metal ions (Ni" , Co , Cu , Zn ) were studied. The fluorescence spectra of most of pyrazolines changed significantly upon addition of divalent transition metal ions ([M]/P = 100). The addition of metal ions causes generally a decrease in optical density of the fluorescence maximum, probably because of electron or energy transfer between metal cation and fluorophore. and for Co+ , Ni+" and Cu+2 ions, typical metal-induced fluorescence quenching was observed while in case of 1- (Isonicotinoyl)-3-(2'-naphthyl)-5-((4-dimethylamino)phenyl)-2-pyrazoline enhancement of the fluorescence was observed upon addition of the Zn2+ ion. Specific fluorescent behaviors of this pyrazolines toward the Zn2+ ion among divalent transition metal ions indicate its potentiality as fluorescent Zn2+ sensors. Donor-acceptor chalcone [1,1 '-(pyridine-2,6-diyl)bis(3-(4-(dimethylamino)phenyl) prop-2-en-l-one)] has been synthesized and its potentiality to use as an ICT (Intramolecular Charge-transfer) probe for selective recognition of zinc ions have been studied in aqueous acetonitrile. Unlike the PET sensors for Zn2+ which show detectable changes only in the emission. This ICT probe showed detection both by UV-Vis and fluorescence spectral monitoring as well.