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

Molecular docking analysis of Carica papaya Linn constituents as antiviral agent

Carica papaya (papaya) fruits are available throughout the world and it is well accepted as food or as a quasi-drug. Aqueous papaya leaves extract have been used as treatment for dengue fever. This prompted us to carry out the docking study on these nine selected ligands (phyto-constituents of papaya) which are carpaine, dehydrocarpaine I and II, cardenolide, p-coumaric acid, chlorogenic acid, caricaxanthin, violaxanthin and zeaxanthin. These phyto-constituents were evaluated on the docking behaviour of dengue serotype 3 RNA-dependent RNA polymerase (RdRp); influenza A (H1N9) virus neuraminidase (NA); chikungunya virus glycoprotein (E3-E2-E1) and chikungunya virus non-structural protein2 (nsP2) protease using Discovery Studio Version 3.1. In addition, molecular physicochemical, drug-likeness, ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) and TOPKAT (Toxicity Prediction by Komputer Assisted Technology) analyses were done. The molecular physicochemical analysis revealed that cardenolide and p-coumaric acid (2 ligands) complied with Lipinski’s rule of five. Dehydrocarpaine II, cardenolide, caricaxanthin, violaxanthin and zeaxanthin all the five ligands were predicted to have plasma protein binding (PPB) effect. Docking studies and binding free energy calculations revealed that p-coumaric acid exhibited very least binding energy irrespective of its target protein. Hence, the results of this present study exhibited the potential of these nine ligands as antiviral agent

Pressing problems and interim solutions at DS Rubber Products Sdn. Bhd.

Michael (General Manager) is having a weekly meeting with the team, the overall production process and flow are running smooth and in an orderly manner. When Sam (Factory Manager) informs Michael that few orders received unable to fulfil within the stipulated time monthly. Michael stunned with this none achieving number and worrying this rate is getting up. Ultimately, the company's objectives are to provide excellent customer experience and maximizing the shareholders' wealth will be impacted. He needs to find out the best solution to handle this none fulfilment of the order, interruption on the production processes, customer dissatisfaction or sourcing alternative suppliers, increase in the production cost and unforeseen impact on the total business. He does concern the existing 34 production lines need to be rearranged the layout, machines prioritization and output maximization, manpower allocation and commissioning. He needs to plan this well before the next meet up with the board of directors. Rubber product business is very competitive and high demanding locally and internationally. The company overseas orders (e.g. Europe, Southeast Asia, and Australasia) keep increasing from month to month. New customers are foreseen to be coming in (at 5% incremental by monthly) with referring to the previous year records. In 2005, the company has obtained ISO 9001:2000 certified by SIRIM QAS international. Eventually, the manufacturing and quality assurance procedures are certified by the ISO 9001:2008 Quality Management System. He shall make sure an excellent customer experience and maximization of the shareholders' wealth is achieved

2-Benzoyl-6-benzylidenecyclohexanone analogs as potent dual inhibitors of acetylcholinesterase and butyrylcholinesterase

In the present study, a series of 2-benzoyl-6-benzylidenecyclohexanone analogs have been synthesized and evaluated for their anti-cholinesterase activity. Among the forty-one analogs, four compounds (38, 39, 40 and 41) have been identified as lead compounds due to their highest inhibition on both AChE and BChE activities. Compounds 39 and 40 in particular exhibited highest inhibition on both AChE and BChE with IC50 values of 1.6 μM and 0.6 μM, respectively. Further structure–activity relationship study suggested that presence of a long-chain heterocyclic in one of the rings played a critical role in the dual enzymes’ inhibition. The Lineweaver–Burk plots and docking results suggest that both compounds could simultaneously bind to the PAS and CAS regions of the enzyme. ADMET analysis further confirmed the therapeutic potential of both compounds based upon their high BBB-penetrating. Thus, 2-benzoyl-6-benzylidenecyclohexanone containing long-chain heterocyclic amine analogs represent a new class of cholinesterase inhibitor, which deserve further investigation for their development into therapeutic agents for cognitive diseases such as Alzheimer

In silico analysis of Mentha pipertia (phyto-constituents) as HMG coa reductase and squalene synthase inhibitors

Mentha piperita has been well known for its hypolipidemic activity. This prompted the present study to be carried out on a selected 12 phyto-constituents of Mentha piperita which are naringin, eriodictyol, eriodictyol 7-glucuronide, eriocitrin, hesperidin, isorohifolin, luteolin 7-glucoside, diosmin, rosmarinic acid, piperitoside, menthoside and caffeic acid. These phyto-constituents were evaluated on the docking behaviour of HMG CoA reductase (HMGR) and Squalene synthase (SQS) using Discovery Studio Version 3.1. In addition, molecular physicochemical, drug-likeness, ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) and TOPKAT (Toxicity Prediction by Komputer Assisted Technology) analyses were done. The molecular physicochemical analysis revealed that eriodictyol, rosmarinic acid and caffeic acid (3 ligands) complied with Lipinski’s rule of five. ADMET analysis showed that eriodictyol and caffeic acid exhibited good intestinal absorption property. Docking studies and binding free energy calculations revealed that menthoside (-70.0 kcal/mol) and piperitoside (-65.32 kcal/mol) exhibited the maximum interaction energy with HMGR and SQS respectively. Caffeic acid exhibited very least binding energy irrespective of its target protein. Caffeic acid showed interaction with Leu546 and Gln212 amino acid residue of HMGR and SQS. Hence, the results of this present study exhibited the potential of these twelve ligands as hypolipidemic agents

Insights on the synthesis of asymmetric curcumin derivatives and their biological activities

Curcumin is a small organic molecule with pleiotropic biological activities. However, its multiple structural-pharmacokinetic challenges prevent its development into a clinical drug. Various structural modifications have been made to improve its drug profile. In this review, we focus on the methods adopted in the synthesis of asymmetric curcumin derivatives and their biological activities and forecast the future of this exciting class of compounds in the field of medicine

Sintesis, penilaian biologi dan kajian dok sebatian auron ke atas enzim xantin oksidase

Perencatan aktiviti xantin oksidase (XO) merupakan satu pendekatan terapeutik yang berkesan dalam rawatan penyakit seperti gout dan hiperurikemia. Selain itu, penggunaan perencat XO juga dapat diluaskan kepada rawatan kecederaan contohnya reperfusi iskemia di pelbagai organ seperti jantung, hati dan buah pinggang. Dalam kajian ini, sebanyak 7 sebatian auron telah disintesis dan diuji ke atas XO dan dibandingkan dengan kawalan positif allopurinol. Sebatian 5e dikenalpasti sebagai sebatian yang paling berpotensi dan mampu merencatkan separuh daripada aktiviti XO pada 33.23 μM diikuti oleh sebatian 5f pada 210.22 μM dan sebatian 5d pada 302.0 μM. Kajian dok molekul telah dijalankan untuk memahami interaksi penting antara auron yang terpilih dengan tapak aktif XO

In vitro and in silico evaluations of diarylpentanoid series as a-glucosidase inhibitor

A series of thirty-four diarylpentanoids derivatives were synthesized and evaluated for their α-glucosidase inhibitory activity. Eleven compounds (19, 20, 21, 24, 27, 28, 29, 31, 32, 33 and 34) were found to significantly inhibit α-glucosidase in which compounds 28, 31 and 32 demonstrated the highest activity with IC50 values ranging from 14.1 to 15.1 µM. Structure-activity comparison shows that multiple hydroxy groups are essential for α-glucosidase inhibitory activity. Meanwhile, 3,4-dihydroxyphenyl and furanyl moieties were found to be crucial in improving α-glucosidase inhibition. Molecular docking analyses further confirmed the critical role of both 3,4-dihydroxyphenyl and furanyl moieties as they bound to α-glucosidase active site in different mode. Overall result suggests that diarylpentanoids with both five membered heterocyclic ring and polyhydroxyphenyl moiety could be a new lead design in the search of novel α-glucosidase inhibitor

Palladium‐catalysed cross‐coupling reactions for the synthesis of chalcones

In this Minireview, we discuss some of the important palladium‐catalysed cross‐coupling reactions utilised in the synthesis of the enone system of chalcones. Examples given here not only exemplify the efficiency and practicality of new C−C bond formation of the enone system via palladium‐catalysed reactions but also reflect some of the revolutionary methods used for the preparation of a more complex and valuable chalcone scaffold which is known to be a privileged structure in the field of medicinal chemistry