Antifungal activity of eugenol analogues. Influence of different substituents and studies on mechanism of action.

Twenty one phenylpropanoids (including eugenol and safrole) and synthetic analogues, thirteen of them new compounds, were evaluated for antifungal properties, first with non-targeted assays against a panel of human opportunistic pathogenic fungi. Some structure-activity relationships could be observed, mainly related to the influence of an allyl substituent at C-4, an OH group at C-1 and an OCH(3) at C-2 or the presence of one or two NO(2) groups in different positions of the benzene ring. All active compounds were tested in a second panel of clinical isolates of C. albicans and non-albicans Candida spp., Cryptococcus neoformans and dermatophytes. The eugenol derivative 4-allyl-2-methoxy-5-nitrophenol (2) was the most active structure against all strains tested, and therefore it was submitted to targeted assays. These studies showed that the antifungal activity of 2 was not reversed in the presence of an osmotic support such as sorbitol, suggesting that it does not act by inhibiting the fungal cell wall synthesis or assembly. On the other hand, the Ergosterol Assay showed that 2 did not bind to the main sterol of the fungal membrane up to 250 µg mL-1. In contrast, a 22% of fungal membrane damage was observed at concentrations = 1 × MIC and 71% at 4× MIC, when 2 was tested in the Cellular Leakage assay. The comparison of log P and MICs for all compounds revealed that the antifungal activity of the eugenol analogues would not to be related to lipophilicity.

New catechol derivatives of safrole and their antiproliferative activity towards breast cancer cells.

Catechols were synthesized from safrole. Nine derivatives were prepared and assessed for antiproliferative effects using different human cell lines. The in vitro growth inhibition assay was based on the sulphorhodamine dye to quantify cell viability. The derivatives 4-allylbenzene-1,2-diol (3), 4 4-[3-(acetyloxy)propyl]-1,2-phenylene diacetate (6) and 4-[3-(acetyloxy)propyl]-5-nitro-1,2-phenylene diacetate (10) showed higher cytotoxicity than the parent compound 2 in tests performed on two breast cancer cell lines (MCF-7 and MDA-MB-231). The IC50 values of 40.2 ± 6.9 µM, 5.9 ± 0.8 µM and 33.8 ± 4.9 µM, respectively, were obtained without toxicity towards dermal human fibroblast (DHF cells).

Synthesis and antiplatelet evaluation of novel aryl-sulfonamide derivatives, from natural safrole.

In the scope of a research program aiming at the synthesis and pharmacological evaluation of novel possible antiplatelet prototype compounds, exploring bioisosterism principles for molecular design, we describe in this paper the synthesis of new aryl-sulfonamides derivatives, structurally similar to known thromboxane A2 receptor antagonists. The synthetic route used to access the new compounds described herein starts from safrole, an abundant Brazilian natural product, which occurs in Sassafras oil (Ocotea pretiosa). The results from preliminary evaluation of these novel aryl-sulfonamide compounds by the platelet aggregation inhibitory test, using rabbit PRP, induced by ADP, collagen, arachidonic acid, and U46619, identified the N-[2-(4-carboxymethoxyphenyl)ethyl]-6-methyl-3,4-methylenedioxyphe nyl- sulfonamido derivative as the most active among them, presenting in IC50 value for the U-46619-induced platelet aggregation in rabbit platelet-rich plasma: 329 microM.

Studies on antiplatelet agents from natural safrole. II. Synthesis and pharmacological properties of novel functionalized oxime O-benzylether derivatives.

In an ongoing research program aiming at the synthesis and pharmacological evaluation of new possible prototype candidates exploring the molecular hybridation and bioisosterism principles for molecular designing, we describe in this paper the design and synthesis of a series of new functionalized oxime O-benzylethers (4a-b) and (14a-b) as antiplatelet agents based on the inhibition of arachidonic acid (AA) cascade enzymes. For the synthesis of these new bioactive derivatives we used safrole (5), a Brazilian abundant natural product, as starting material. The platelet anti-aggregating evaluation of these oxime O-benzylether compounds (4a-b) and (14a-b) in model induced by ADP, collagen and AA, has permitted to evidence an antithrombotic profile to these new derivatives, being the most active the derivative methyl [[3,4-methylenedioxyphenyl]methylene]amino]oxy]-4-methylenephenylacet ic acid (14a).

Quaternary ammonium salt derivatives of allylphenols with peripheral analgesic effect.

Ammonium salt derivatives of natural allylphenols were synthesized with the purpose of obtaining potential peripheral analgesics. These drugs, by virtue of their physicochemical properties, would not be able to cross the blood brain barrier. Their inability to enter into the central nervous system (CNS) should prevent several adverse effects observed with classical opiate analgesics (Ferreira et al., 1984). Eugenol (1) O-methyleugenol (5) and safrole (9) were submitted to nitration, reduction and permethylation, leading to the ammonium salts 4, 8 and 12. Another strategy applied to eugenol (1), consisting in its conversion to a glycidic ether (13), opening the epoxide ring with secondary amines and methylation, led to the ammonium salts 16 and 17. All these ammonium salts showed significant peripheral analgesic action, in modified version of the Randall-Sellito test (Ferreira et al., 1978), at non-lethal doses. The ammonium salt 8 showed an activity comparable to that of methylnalorphinium, the prototype of an ideal peripheral analgesic (Ferreira et al., 1984).

Quaternary ammonium salt derivatives of allylphenols with peripheral analgesic effect

Ammonium salt derivatives of natural allylphenols were synthesized with the purpose of obtaining potential peripheral analgesics. These drugs, by virtue of their physicochemical properties, would not be able to cross the blood brain barrier. Their inability to enter into the central nervous system (CNS) should prevent several adverse effects observed with classical opiate analgesics (Ferreira et al., 1984). Eugenol (1) O-methyleugenol (5) and safrole (9) were submitted to nitration, reduction and permethylation, leading to the ammonium salts 4, 8 and 12. Another strategy applied to eugenol (1), consisting in its conversion to a glycidic ether (13), opening the epoxide ring with secondary amines and methylation, led to the ammonium salts 16 and 17. All these ammonium salts showed significant peripheral analgesic action, in modified version of the Randall-Sellito test (Ferreira et al. 1978), at non-lethal doses. The ammonium salt 8 showed an activity comparable to that of methylnalorphinium, the prototype of an ideal peripheral analgesic (Ferreira et al., 1984).