DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF FUNCTIONALIZED FLAVONOIDS DERIVATIVES

Abstract

The thesis entitled “Design, Synthesis and Biological Evaluation of Functionalized Flavonoids Derivatives” is reported in five chapters. The present work is aimed to design and synthesis of novel flavonoids based derivatives involving C-C, C-O, C-N, C-S bonds formation using different reactions like Prins cyclization, thia- Michael addition, and click reaction. Novel synthesized compounds were characterized using different analytical techniques such as 1H NMR, 13C NMR, 2D NMR, IR, mass, CHNS and X-ray diffraction and their biological evaluations were reported as antimicrobials and anti-proliferative applications. The thesis has been divided into five chapters for the sake of convenience and clarity, and organized as follows: Chapter 1: Introduction Flavonoids are found in most of the higher plants as secondary metabolites and are water soluble due to polyphenolic nature. These naturally occurring compounds are widely distributed in plants like vegetables, tea, soya bean, berries and other citrus fruits as dietary sources. They have exhibited antioxidant and chelating properties so have many health promoting effects. Some of the activities attributed to flavonoids include anti-allergic, anti-cancer, antioxidant, anti-inflammatory and anti-viral. Flavonoids as central core containing compounds are used as drugs such as xanthokeismins A-C, and dimefine for the treatment of bronchial asthma. This chapter describes classification of flavonoids and a brief literature review of flavonoids biosynthesis and different synthetic methods that include Baker-Venkataraman rearrangement, Claisen-Schmidt condensation, Friedel-Crafts acylation, Microwave assisted synthesis, Algar–Flynn–Oyamada reaction, Auwers synthesis, Allan–Robinson reaction, and Suzuki-Miyaura reaction. Flavonoids are central core structures in natural and synthetic compounds such as xanthohumol, rhuschalcone, amentoflavone, robustaflavone, ochnaflavone their synthesis and applications such as anti-cancer, antioxidant, anti-inflammatory and anti-microbial were discussed. Similarly, the effects of different substituents on biological activity such as prenyl, geranyl, hydroxyl, amino, methoxy, methyl and hydroxyl on flavonoids were discussed. Functionalized tetrahydropyrans (THPs) are key structural motifs in many natural products such as (+)-neopeltolide, phorboxazole A & B, and pheromones. They have shown many promising biological applications including in vivo antinociceptive activity, in vitro anti-cancer, anti- iv hypertensive, anti-bacterial and anti-fungal activities. Flavonoid based THPs are also precursors of drugs like tetrahydrocannabinol, dimethylheptylpyran, etc. Therefore, various reaction strategies have been explored for the stereoselective synthesis with proper functionalization such as hetero- Diels-Alder method, oxidative C−H bond activation, Prins cyclization, etc. Among them, Prins cyclization is found the best method for the pyran ring construction in high yields under mild reaction conditions. Applications of Prins cyclization strategy in total synthesis of natural products such as neopeltolide, and epicalyxin F, were discussed. Scheme 1: Total synthesis of epicalyxin F via Prins cyclization. Chapter 2: Synthesis of 2,6-Disubstituted-4-Tosyloxytetrahydropyrans via Prins cyclization Part-A: Efficient, Highly Diastereoselective MS 4 Å-Promoted One-pot, Three-Component Synthesis of 2,6-Disubstituted-4-Tosyloxytetrahydropyrans via Prins cyclization Naseem Ahmed* and Naveen Kumar Konduru, Beilstein J. Org. Chem. 8 (2012) 177–185 In this part, a novel synthetic method is demonstrated for the synthesis of 2,6-disubstituted- 4-tosyloxytetrahydropyrans via Prins cyclization using aromatic homoallylic alcohols, aldehydes, ptoluenesulfonic acid and MS 4 Å under optimized reaction conditions. This methodology proved to be versatile enough to provide an array of symmetrical and unsymmetrical tetrahydropyran derivatives with moderate to excellent yields (72–96%) within 20–90 min. under mild reaction condition. Further, deprotection of 4-tosyl group with Mg–MeOH afforded 4- hydroxytetrahydropyrans. All products were fully characterized by FT-IR, 1H NMR, 13C NMR, CHNS and stereochemistry of products determined by 1H NMR and NOESY techniques. Scheme 2: Synthesis of 4-tosyloxy and 4-hydroxy tetrahydropyrans. v Part B: Synthesis of Flavonoids based Novel Tetrahydropyran Conjugates (Prins Products) and Their Antiproliferative Activity Against Human Cancer Cell Lines Naseem Ahmed,a* Naveen Kumar Konduru,a Sarfaraz Ahmad,b Mohammad Owais,b Eur. J. Med. Chem.2013 Accepted with minor review. In this part, the synthesis and characterization of novel flavonoid-tetrahydropyran conjugates and their anti-proliferative activity against human cancer cell lines were reported. Here products were synthesized in moderate to excellent yields (72–96%) and high diastereoselectivity under optimized reaction condition using aromatic homoallylic alcohol, flavonoid based aldehyde, ptoluenesulfonic acid and MS 4 Å in CHCl3. Deprotection of tosyl group and the reaction with cinnamoyl chloride resulted in 4-cinnamate tetrahydropyrans. Products were fully characterized by FT-IR, 1H NMR, 13C NMR, HRMS and stereochemistry of products were determined by 1H NMR, COSY, HMBC and NOESY techniques and compounds were evaluated for their anti-proliferative activity in vitro against 3 human cancer cell lines (Hep3β, MCF-7 and Hela), most of the compounds showed good anti-proliferative activities. Scheme 3: Synthesis of flavonoid based 4-tosyloxy, 4-hydroxy and 4-cinnamate tetrahydropyrans. Chapter 3: Design and Efficient Synthesis of Functionalized Flavone-Triazole- Tetrahydropyran Conjugates via Click Chemistry Manuscript under preparation. In this chapter, a mild and efficient synthesis of functionalized flavone-triazoletetrahydropyran conjugates was reported via click reaction. We performed reaction between 4- azidotetrahydropyran and flavone based alkynes under optimized Cu-catalyzed 1,3-dipolar cycloaddition reaction condition. The products 5-iodo and 5-H-1-(tetrahydropyran)-1,2,3-triazol-4- (3-methoxylflavone) derivatives were obtained in excellent yields (90-98%) within 1-3 h. Pdvi catalyzed Suzuki cross-coupling reaction of 5-iodo-1,2,3-triazoles with phenylboronic acids were performed to afford 5-phenyl-1-(tetrahydropyran)-1,2,3-triazol-4-(3-methoxylflavone) derivatives in high yields (93-95%) within 4–5h. Scheme 4: Synthesis of 5-H, 5-I and 5-phenyl triazole derivatives. All products were fully characterized by FT-IR, 1H NMR, 13C NMR, HRMS and stereochemistry of products determined by 1H NMR, NOESY and single crystal X-ray analysis. Figure 1: ORTEP diagram of 3-((1-((2S,4S,6R)-2-(4-bromophenyl)-6-(4-chlorophenyl)tetrahydro- 2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)-2-p-tolyl-4H-chromen-4-one. Chapter 4: Regioselective Opening of Chalcone Epoxides with Nitrogen Heterocycles using Indium(III) Chloride as an Efficient Catalyst Naveen Kumar Konduru and Naseem Ahmed,* Synth. Commun. 43 (2013) 2008-2018. In this chapter, the synthesis and characterization of chalcone based nitrogen heterocycles were reported by opening of chalcone epoxides with different nitrogen heterocycles (indole, 2- methyl indole, pyrrole) in the presence of suitable Lewis acid catalyst. Optimization of reaction conditions and screening of Lewis acids gave Indium(III) chloride at 20 mol% the best catalyst and dichloromethane as suitable solvent for the regioselective epoxide ring opening which gave vii products in good yields (60-88%). All products were fully characterized by FT-IR, 1H NMR, 13C NMR, GC-MS and HRMS. Scheme 5: Regioselective opening of chalcone epoxides with nitrogen heterocycles. Chapter 5: Synthesis of Chalcone based Sulfones and Bisulfones and their Antimicrobial Evaluation Part-A: Synthesis, Antibacterial and Antifungal Evaluation of some Chalcone based Sulfones and Bisulfones Published in: Naveen Kumar Konduru,a Sunita Dey,a Mohammad Sajid,b Mohammad Owais,b Naseem Ahmed,a* Eur. J. Med. Chem. 59 (2013) 23-30. In this part, the synthesis and characterization of chalcone based sulfone and bisulfone derivatives and evaluation of their antimicrobial activity were reported. Chalcone sulfides and bisulfides were synthesized using chalcone, thiophenol and sodium metal at room temperature, followed by oxidation of chalcone sulfides with m-CPBA under optimal conditions affords chalcone sulfones and bisulfones. All synthesized compounds were fully characterized using analytical techniques such as FT-IR, 1H NMR, 13C NMR, and CHNS. Synthesized chalcone sulfones and bisulfones were evaluated for their antimicrobial activities against yeast (A. niger, C. albicans), Gram (+) bacteria (B. subtilis, S. aureus) and Gram (−) bacteria (P. aeruginosa,, S. typhimurium). All compounds have shown moderate to high antimicrobial activity. Scheme 6: Synthesis of chalcone based sulfones and bisulfone. viii Part-B: Design, Synthesis and Antimicrobial Activities of Novel Ferrocenyl and Organic Chalcone based Sulfones and bis-Sulfones Communicated in: Naveen Kumar Konduru,a Sarfaraz Ahmad,b Mohammad Owais,b Naseem Ahmeda* J. Heterocycle Chemistry, Under Review. In this part, the synthesis and characterization of a series of novel ferrocenyl, organic chalcone based sulfone derivatives and evaluation of their antimicrobial activities against important pathogens were reported. The products were afforded with excellent yields (91-95%). All synthesized compounds were fully characterized using analytical techniques such as FT-IR, 1H NMR, 13C NMR, and HRMS. Synthesized compounds were tested for antimicrobial activity [A. niger, C. albicans, A. fumigatus, C. neoformans, C. parapsilosis and C. tropicalis (yeast), B. subtilis, S. aureus and L. monocytogenes (Gram (+) bacteria) and P. aeruginosa, K. pneumonia, E. coli, and P. vulgaris (Gram (-) bacteria) strains]. Majority of the synthesized compounds have shown good activity. Scheme 7: Synthesis of ferrocenylchalcone based sulfones.