The Synthesis and Bioactivity of 2,6-Bisbenzylidenecyclohexanone, Pyrazoline, Chalcone and Oxadiazole Derivatives and Computational Studies on Some of These Compounds

In the first part of this thesis fulfillment, a series of forty four 2,6-bisbenzylidenecyclohexanone, pyrazoline, pyrazole and isoxazole derivatives were synthesized and evaluated for inhibitory activities on IFN-γ/LPS-activated RAW 264.7 cells and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity. Three compounds 4-8, 4-9 and 4-11a possessed significant nitric oxide (NO) inhibitory activities as compared to N-Nitro-L-Arginine Methyl Ester (L-NAME) and curcumin with an IC50 value of 6.68 ± 0.16 μM, 6.09 ± 0.46 μM and 6.84 ± 0.12 μM, respectively. Apparently, the suppression effect upon NO secretion was not due to cell death since the active compounds did not suppress the cell viability in close proximity to the IC50 of NO inhibition. Meanwhile compound 4-11 (IC50 = 13.27 ± 1.78 μM)bearing adjacent hydroxyl groups recorded the highest radical scavenging activity as compared to quercetin (IC50 = 21.46 ± 0.85 μM). The binding mode of compound 4-8 (2,6-bis(4-hydroxy-3-methoxybenzylidene)cyclohexanone, BHMC) at the active site of p38α MAP kinase (PDB code 1a9u) was investigated using AUTODOCK 4.2 program. Both the hydroxyl groups of BHMC were involved in hydrogen bonding with residues, including Methionine 109 (2.086Å) and Phenylalanine 169 (2.137Å) with the calculated free binding energy of -6.96 kcal/mol. One of the phenyl groups was clearly seen occupying the hinge region, while the other ring filled the cavity at the back of the ATP-site. In the second part of this thesis, a further forty six chalcone derivatives were synthesized and evaluated for anti-inflammatory activity on RAW 264.7 cells. Among these compounds, chalcones bearing the furanyl group showed remarkable results as anti-inflammatory agents. Both compounds 5-2d and 5-2j were identified as the most potent NO inhibitor on IFN-γ/LPS-activated RAW 264.7 cells with IC50 values of 2.51 ± 0.42 μM and 2.26 ± 0.47 μM, respectively. In order to examine the structure-activity relationship, a 3D QSAR analysis was carried out by comparative molecular field analysis (CoMFA) method on the selected chalcones. Partial least square analysis produced a statistically coherent model with good predictive value, r2 = 0.989 and a good cross validated value, q2 = 0.583. The binding mode of compound 5-2a (3-(2-hydroxyphenyl)-1-(5-methylfuran-2-yl)prop-2-en-1-one, HMP) at the active site of p38α MAP kinase (PDB code 1a9u) was investigated using AUTODOCK 4.2 program. The hydroxyl group was involved in hydrogen bonding with the backbone amide of Methionine 109 nitrogen atom with the calculated free binding energy of -6.15 kcal/mol. The methylfuranyl moiety was clearly seen occupying the hydrophobic back pocket where the p38α gatekeeper residue, Threonine 106 resided. In the final part of the thesis, a series of twenty four oxadiazole and triazolothiadiazole derivatives were synthesized and evaluated for their mushroom tyrosinase inhibitory activity. Five derivatives were found to display high inhibition activity ranging from 0.87 to 1.49 μM. Compound 6-5 exhibited the highest activity with IC50 value of 0.87 ± 0.16 μM. The in silico protein-ligand docking using AUTODOCK 4.1 was successfully performed on compound 6-5 with significant binding energy value of -5.58 kcal/mol. The docking results also showed that the tyrosinase inhibition might be due to the metal chelating effect of thione functionality in compounds 6-1 until 6-5. Further studies revealed that the presence of hydrophobic groups such as cycloamine derivatives played an important role in the inhibition. The piperazine moiety in compound 5 appeared to be involved in an extensive hydrophobic contact and a 2.9 Å hydrogen bond with residue Glutamic acid 182 in the active site.

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