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Thymol is a natural product, which has antioxidant activity. 4-Morpholinomethyl-2-isopropyl-5-methylphenol (THMO), and 4-Pyrrolidinomethyl-2-isopropyl-5-methylphenol (THPY) were synthesized by reacting thymol with formaldehyde and, respectively, morpholine or pyrrolidine. Since there is a relationship between the antioxidative status and incidence of human disease, antisuperoxidation, free radical scavenger activity, and anti-lipid peroxidation of the thymol analogues were determined by xanthine oxidase inhibition, cytochrome C system with superoxide anion releasing with formyl-Met-Leu-Phe (fMLP)/cytochalasin (CB) or phorbol myristate acetate (PMA) activating pathway in human neutrophils. All compounds studied had antioxidant activity. Mannich bases derived from thymol were generally found to be more potent compounds than thymol. THMO demonstrated the greatest antioxidant activity with IC 50 values for xanthine oxidase inhibition and anti-lipid peroxidation being 2172.78 and 61.2975.83 mM, respectively. Moreover, since oxidative stress by free radical regulates the activity of L-type Ca 2þ channel, the whole-cell configuration of the patch-clamp technique was used to investigate the effect of THMO upon ionic currents within NG108-15 cells. THMO (10 mM) suppressed the peak amplitude of L-type Ca 2þ inward current (I Ca,L ), indicating that the antioxidative potential of the thymol analogues might be related to calcium current inhibition. The present studies suggest that THMOdependent antioxidant and calcium ion current inhibition activity may be useful in treating free radicalrelated disorders. Drug Dev Res 64:195-202, 2005.

4-Piperidinomethyl-2-isopropyl-5-methylphenol (THPI) was synthesized by reaction of thymol with piperidine and formaldehyde. The biological effect of THPI on superoxide anion scavenging activity, antiplatelet activity and calcium current inhibition were investigated. THPI (50 microM) was shown to be a scavenger of superoxide radicals in human neutrophils stimulated with N-formyl-Met-Leu-Phe (66% inhibition). Since superoxide anions are essential for platelet aggregation and L-type Ca2+-channel activity, we further found that THPI inhibited platelet aggregation induced by arachidonic acid (IC50 46.80+/-6.88 microM). The effect of THPI on Ca2+ current in NG108-15 cells was investigated using the whole-cell voltage-clamp technique. THPI inhibited voltage-dependent L-type Ca2+ current (ICa, L). The IC50 value of THPI-induced inhibition of ICa, L was 3.60+/-0.81 microM. THPI caused no change in the overall shape of the current-voltage relationship of ICa, L. This indicates that THPI is an inhibitor of ICa, L in NG108-15 cells. Therefore, the channel-blocking properties of THPI may contribute to the underlying mechanism by which it affects neuronal or neuroendocrine function. Furthermore, no significant cytotoxic effects of THPI (0.3-50 microM) were observed in NG108-15 cells. The results indicate that THPI is a potential reactive oxygen species scavenger and may prevent platelet aggregation or inhibit L-type Ca2+-channel activity, possibly by scavenging reactive oxygen species.

A silica‐base chiral stationary phase (CSP) derived from L‐alanyl‐ and piperidinyl‐disubstituted cyanuric chloride was prepared for the enantioseparation of methyl esters of N‐(3,5‐dinitrobenzoyl)amino acids and amino alcohols. This CSP provides good chiral recognition and effective separation of enantiomers of both methyl esters of N‐(3,5‐dinitrobenzoyl)amino acids, except for proline, and N‐(3,5‐dinitrobenzoyl)amino alcohols by high‐performance liquid chromatography. The enantioselectivity depends mainly on three preferential interactions which include a π‐π interaction and two hydrogen‐bonding interactions. However, steric interaction between substituents attached to the chiral center of chiral selectands and the chiral selector also plays a significant role in chiral recognition. Comparison of chromatographic results of the CSP prepared in this study with those of the CSP containing pyrrolidinyl group attached to the s‐triazine moiety, reported previously (J. Chromatogr. A, 722 (1996) 189), reveals that influences of steric interaction and the basic nature of piperidinyl substituent attached to the s‐triazine ring of the chiral selector on chiral discrimination may not be neglected.

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