Thummaruk Suksrichavalit

Copper complexes of pyridine derivatives with superoxide scavenging and antimicrobial activities

Superoxide anions are reactive oxygen species that can attack biomolecules such as DNA, lipids and proteins to cause many serious diseases. This study reports the synthesis of copper complexes of nicotinic acid with related pyridine derivatives. The copper complexes were shown to possess superoxide dismutase (SOD) and antimicrobial activities. The copper complexes exerted SOD activity in range of 49.07-130.23 microM. Particularly, copper complex of nicotinic acid with 2-hydroxypyridine was the most potent SOD mimic with an IC(50) of 49.07 microM. In addition, the complexes exhibited antimicrobial activity against Bacillus subtilis ATCC 6633 and Candida albicans ATCC 90028 with MIC range of 128-256 microg/mL. The SOD activities were well correlated with the theoretical parameters as calculated by density functional theory at the B3LYP/LANL2DZ level of theory. Interestingly, the SOD activity of the copper complexes was demonstrated to be inversely correlated with the electron affinity, but was well correlated with both HOMO and LUMO energies. The vitamin-metal complexes described in this report are great examples of the value-added benefits of vitamins for medicinal applications.

Copper Complexes of Nicotinic-Aromatic Carboxylic Acids as Superoxide Dismutase Mimetics

Nicotinic acid (also known as vitamin B3) is a dietary element essential for physiological and antihyperlipidemic functions. This study reports the synthesis of novel mixed ligand complexes of copper with nicotinic and other select carboxylic acids (phthalic, salicylic and anthranilic acids). The tested copper complexes exhibited superoxide dismutase (SOD) mimetic activity and antimicrobial activity against Bacillus subtilis ATCC 6633, with a minimum inhibition concentration of 256 µg/mL. Copper complex of nicotinic-phthalic acids (CuNA/Ph) was the most potent with a SOD mimetic activity of IC50 34.42 µM. The SOD activities were observed to correlate well with the theoretical parameters as calculated using density functional theory (DFT) at the B3LYP/LANL2DZ level of theory. Interestingly, the SOD activity of the copper complex CuNA/Ph was positively correlated with the electron affinity (EA) value. The two quantum chemical parameters, highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO), were shown to be appropriate for understanding the mechanism of the metal complexes as their calculated energies show good correlation with the SOD activity. Moreover, copper complex with the highest SOD activity were shown to possess the lowest HOMO energy. These findings demonstrate a great potential for the development of value-added metallovitamin-based therapeutics.

Synthesis and Theoretical Study of Molecularly Imprinted Nanospheres for Recognition of Tocopherols

Molecular imprinting is a technology that facilitates the production of artificial receptors toward compounds of interest. The molecularly imprinted polymers act as artificial antibodies, artificial receptors, or artificial enzymes with the added benefit over their biological counterparts of being highly durable. In this study, we prepared molecularly imprinted polymers for the purpose of binding specifically to tocopherol (vitamin E) and its derivative, tocopherol acetate. Binding of the imprinted polymers to the template was found to be two times greater than that of the control, non-imprinted polymers, when using only 10 mg of polymers. Optimization of the rebinding solvent indicated that ethanol-water at a molar ratio of 6:4 (v/v) was the best solvent system as it enhanced the rebinding performance of the imprinted polymers toward both tocopherol and tocopherol acetate with a binding capacity of approximately 2 mg/g of polymer. Furthermore, imprinted nanospheres against tocopherol was successfully prepared by precipitation polymerization with ethanol-water at a molar ratio of 8:2 (v/v) as the optimal rebinding solvent. Computer simulation was also performed to provide mechanistic insights on the binding mode of template-monomer complexes. Such polymers show high potential for industrial and medical applications, particularly for selective separation of tocopherol and derivatives.

Modeling the LPS Neutralization Activity of Anti-Endotoxins

Bacterial lipopolysaccharides (LPS), also known as endotoxins, are major structural components of the outer membrane of Gram-negative bacteria that serve as a barrier and protective shield between them and their surrounding environment. LPS is considered to be a major virulence factor as it strongly stimulates the secretion of pro-inflammatory cytokines which mediate the host immune response and culminating in septic shock. Quantitative structure-activity relationship studies of the LPS neutralization activities of anti-endotoxins were performed using charge and quantum chemical descriptors. Artificial neural network implementing the back-propagation algorithm was selected for the multivariate analysis. The predicted activities from leave-one-out cross-validation were well correlated with the experimental values as observed from the correlation coefficient and root mean square error of 0.930 and 0.162, respectively. Similarly, the external testing set also yielded good predictivity with correlation coefficient and root mean square error of 0.983 and 0.130. The model holds great potential for the rational design of novel and robust compounds with enhanced neutralization activity.

Antimicrobial and antioxidative activities of 1-adamantylthio derivatives of 3-substituted pyridines

Diverse biological activities of sulfur containing pyridines were reported. To investigate for new lead compounds, thus, 1-adamantylthiopyridines bearing 3-substituents (OEt, OAc, NAc2, Br and OH) were prepared and evaluated for antimicrobial and antioxidative activities. The antimicrobial assay against 27 strains of microorganisms was performed using agar dilution method. The results show that all the tested 2-(1-adamantylthio)-3-ethoxypyridine (4a), 2-(1-adamantylthio)-3-acetoxypyridine (4b), N-acetyl-2-(1-adamantylthio)-3-acetamidopyridine (4c), 2-(1-adamantylthio)-3-bromopyridine (4d), 2-(1-adamantylthio)-5-hydroxypyridine (5) and 3-(1-adamantylthio)-5-bromopyridine (6) exhibit antigrowth activity on Streptococci at 30 μg/mL. Particularly, the thiopyridines 4c, 5 and 6 are the most active compounds, displaying complete inhibition against β-hemolytic Streptococcus group A at 30 μg/mL. These pyridyl sulfides 4a-d, 5 and 6 represent a new group of antimicrobial agents. Antioxidative activity was analyzed using the DPPH assay. The sulfides 4a-d, 5 and 6 show only a weak antioxidative activity. In contrast the 2-(1-adamantylthio)-3-bromopyridine (4d) shows the highest radical scavenging activity.

Investigation on biological activities of anthranilic acid sulfonamide analogs

In the previous studies, the cytotoxicities of anthranilate sulfonamides were investigated. Herein, the bioactivities of 4-substituted (X = NO2, OCH3, CH3, Cl) benzenesulfonamides of anthranilic acid (5-8) are reported. The results revealed that all sulfonamides selectively exerted antifungal activity (25-50 % inhibition) against C. albicans at 4 μg/mL. Furthermore, compounds 6 and 8 show antioxidative (SOD) activity. These sulfonamides, except for 6, selectively display cytotoxic effects toward MOLT-3 cells. It is interesting to note that sulfonamides with electron withdrawing substituent (5, X = NO2) exhibited the highest cytotoxicity. This study provided preliminary structure-activity relationship of the anthranilic sulfonamides that is useful for further in-depth investigation.

Bioactive 4-hydroxycinnamide and bioactivities of Polyalthia cerasoides

Constituents from Polyalthia cerasoides, stem bark methanol extract, were previously documented. This study reports the first isolation of bioactive N-(4-hydroxy-β-phenethyl)-4-hydroxycinnamide (1) from ethyl acetate extract of the plant species including stigmasterol and a mixture of triterpenes from hexane and dichloromethane extracts. Trace essential elements were found in the hexane extract in ppm level. The plant extracts were evaluated for their antimicrobial and antioxidative activities. The dichloromethane extract displayed the highest activity against Corynebacterium diphtheriae NCTC 10356 with MIC of 32 µg/mL, as well as, the highest SOD activity with an IC50 of 4.51 µg/mL.

Synthesis of a “clickable” Angiopep-conjugated p-coumaric acid for brain-targeted delivery

Overexpression of free radicals in the brain is emerging as important markers in the etiology of neurodegenerative diseases including Parkinson’s disease, Alzheimer’s disease, and stroke. Numerous antioxidants with protective effect on neuronal injuries under oxidative stress are often limited to penetrate the blood–brain barrier (BBB). Angiopep-2 is the ligand of low-density lipoprotein receptor-related protein expressed on the BBB possessing high transcytosis capacity and parenchymal accumulation. In this study, novel Angiopep-conjugated p-coumaric acid (3) was synthesized, using the Click chemistry, as a potential antioxidant for the protection of the brain under oxidative stress. The clickable Angiopep (3) was synthesized by Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction of the terminal acetylene-modified Angiopep and azide of p-coumaric acid. The Angiopep-conjugated compound (3) showed antioxidant potency and non-cytotoxic effect toward brain endothelial cells (BECs). Obviously, the penetration and BECs protection of 3 were higher than that of the unconjugated p-coumaric acid. The results establish the bio-conjugation of antioxidant and Angiopep with enhanced protective effect on the BECs under oxidative stress. The findings provide great potential for the development of neurotherapeutics with increased brain penetration.