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Cinnamic acids have been identified as interesting compounds with antioxidant, anti-inflammatory and cytotoxic properties. In the present study, simple cinnamic acids were synthesized by Knoevenagel condensation reactions and evaluated for the above biological activities. Compound 4ii proved to be the most potent LOX inhibitor. Phenylsubstituted acids showed better inhibitory activity against soybean LOX, and it must be noted that compounds 4i and 3i with higher lipophilicity values resulted less active than compounds 2i and 1i. The compounds have shown very good activity in different antioxidant assays. The antitumor properties of these derivatives have been assessed by their 1/IC 50 inhibitory values in the proliferation of HT-29, A-549, OAW-42, MDA-MB-231, HeLa and MRC-5 normal cell lines. The compounds presented low antitumor activity considering the IC 50 values attained for the cell lines, with the exception of compound 4ii. Molecular docking studies were carried out on cinnamic acid derivative 4ii and were found to be in accordance with our experimental biological results.

Lipoxygenase plays an essential role in the biosynthesis of the leukotrienes. Leukotrienes, as LO metabolites of arachidonic acid (AA), have been implicated as mediators in the pathophysiology of inflammatory diseases, host defense reactions and to play important role in the propagation of the diseases states, exacerbating the local events and ultimately leading to tissue damage. Simple stable molecules containing the hydroxamic acid functionality have been shown to inhibit 5-lipoxygenase. In fact, several hydroxamates are orally active inhibitors of the enzyme as determined by their ability to block the biosynthesis of leukotriene in vivo. In order to establish the inhibitory utility of simple hydroxamates several omega-phenylalkyl and omega-naphthylalkyl hydroxamic acids were synthesized. In an attempt to expand and delineate these results we tried to synthesize some more for a further pharmacochemical study. Since lipophilicity is a significant physicochemical property determining distribution, bioavailability, metabolic activity and elimination, we tried to determine experimentally their lipophilicity from RPTLC method. The compounds are tested in vitro on: a) soybean lipoxygenase inhibition, b) interaction with 1,1-diphenyl-2-picryl-hydrazyl (DPPH) stable free radical, c) the HO* radical mediated oxidation of DMSO, d) inhibition of lipid peroxidation, e) scavenging of superoxide anion radicals f) interaction with glutathione and g) in vivo for the inhibition of carrageenin induced rat paw edema. The compounds have shown important antioxidant activity, medium anti-inflammatory activity and potent inhibition of soybean lipoxygenase as a result of their physichochemical features.

This paper contains a quantitative structure activity relationship (QSAR) study for lipoxygenase (LO) inhibitors. It reveals that in almost all cases, the clog P parameter plays an important part in the QSARs (linear or bilinear model). In some cases the steric factors such as the overall molar refractivity (CMR) or the substituents molar refractivity (MR) (linear or parabola) are important. Electronic effects are comparatively unimportant. The study shows that log P as calculated from the Clog P program is suitable for this form of QSAR study.