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Title:	Synthesis and biological evaluation of chalcone derivatives and curcumin analogues
Authors:	Syed Nasir Abbas Bukhari (P53365)
Supervisor:	Malina Jasamai, Dr.
Keywords:	Universiti Kebangsaan Malaysia -- Dissertations Dissertations, Academic -- Malaysia Curcumin-pharmacology Curcumin-therapeutic use
Issue Date:	25-Apr-2013
Description:	Curcumin is the most studied curcuminoid of the Curcuma species and is well known for its numerous biological and pharmacological activities. However, its poor bioavailability hinders the progress of curcumin to be developed further as a drug entity. Chalcones are the principal precursors for the biosynthesis of flavonoids and isoflavonoids and they consist of a three carbon α, β-unsaturated carbonyl system. Synthetic curcumin analogues and chalcone derivatives are well studied for various pharmacological activities but their effects on the immune system are not fully explained. In the present study, 57 curcumin analogues and 40 chalcone derivatives were investigated for their inhibitory effects on reactive oxygen species (ROS) production, chemotaxis and phagocytosis of human neutrophils. Some of the compounds were also tested for antitubercular activity against replicating and nonreplicating phenotypes of Mycobacterium tuberculosis (M.tb). Of the compounds tested, 18 were newly synthesized curcumin analogues and 11 were newly synthesized chalcone derivatives which were synthesized by Claisen Schmidt condensation reaction. Their effects on ROS production was evaluated using luminol and lucigenin-based chemiluminescence assay while their inhibition of isolated polymorphonuclear leucocytes (PMNs) chemotaxis and phagocytosis ability were investigated using the Boyden chamber technique and Phagotest kit, respectively. Antitubercular activity was evaluated by Microplate Alamar Blue Assay (MABA) and Low Oxygen Recovery Assay (LORA). Among the curcumin analogues, nine were very active against PMN chemotaxis with IC50 values ranging from 1.9 to 6.4 μM. Of the chalcone derivatives, three pyrazolines and one isoxazoles showed strong activity against PMN chemotaxis with IC50 values ranging from 5.6 to 8.4 μM. Amongst the newly synthesized curcumin analogues tested, seven analogues showed less phagocytic activity than curcumin. Among the compounds tested, six curcumin analogues and six chalcone derivatives showed remarkable inhibition of intracellular ROS production from human whole blood. Preliminary screening of the pyrazolines and isoxazoles derivatives on the whole blood revealed that compounds 4.76 and 4.77 exhibited high inhibitory activity for luminol-enhanced chemiluminescence with IC50 values of 9.4 and 18.1 μM, respectively. Seven curcumin analogues and one chalcone derivative exhibited strong inhibition of ROS production of PMNs with IC50 values below 9.6 μM. Curcumin analogues and chalcone derivatives showed moderate effect against MTB with MIC values ranging from 18.3 to 95.7 μg/mL. Structure activity analyses indicate that compounds bearing 2-methyl-N-ethyl-N-(2-cyanoethyl)-4- amino, 4-diethlyamino, 2,3-dimethoxy and N-methyl-N-(2-hydroxyethyl)-4-amino substitutions showed strong activity against PMN chemotaxis and ROS production. Synthetic compounds with cyclohexanone ring system were found to be more active then compounds bearing acetone and cyclopentanone ring systems for inhibition of ROS production. These results suggest that some of these synthetic compounds were able to modulate the innate immune response of phagocytes at different steps, indicating their potential as a source of new immunomodulatory agents,Certification of Master's/Doctoral Thesis" is not available
Pages:	217
Call Number:	WB925.S982s
Publisher:	UKM, Kuala Lumpur
Appears in Collections:	Faculty of Pharmacy / Fakulti Farmasi

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