Synthesis of new trypanocidal agents from the hybridisation of metronidazole and eugenol analogues.

Nitroimidazole compounds are well-known bioactive substances, and the structural activity relationship has been reported whereby the position of the nitro group within the imidazole ring has a large influence on the activity. This study focuses on synthesising new trypanocidal agents from the hybridisation of metronidazole with different natural phenols (eugenol, dihydroeugenol and guaiacol). Two different coupling methodologies have been explored in order to analyse the influence of the connector on bioactivity: i) classic direct esterification (AD compounds) and ii) "click" chemistry using a triazole connector (AC compounds). The in vitro trypanocidal tests show good results for both AC and AD hybrid compounds against both epimastigote and trypomastigote forms of T. cruzi. In silico studies showed positive data for most of the synthesised compounds and, in general present low toxicological risks. The AC compounds present lower ClogP (lipophilicity) values than those found for the AD series and higher TPSA (topological polar surface area) values, suggesting lower lipophilicity may be related to the presence of the triazole connector. The AD series compounds have higher Drug Score values than the AC series derivatives, suggesting better general properties for a pharmacological action.

Synthesis and Anti-Oomycete Activity of 1-Sulfonyloxy/Acyloxydihydroeugenol Derivatives.

Endeavor to discover biorational natural products-based fungicides, two series (26) of novel 1-sulfonyloxy/acyloxydihydroeugenol derivatives (3a-p and 5a-j) were prepared and assessed for their fungicidal activity against P. capsici Leonian, in vitro. Results of fungicidal activity revealed that, among all compounds, especially compounds 3a, 5c, and 5e displayed the most potent anti-oomycete activity against P. capsici with EC50 values of 69.33, 68.81, and 67.77 mg/L, respectively. Overall, the anti-oomycete activities of 1-acyloxydihydroeugenol derivatives (5a-j) were higher than that of 1-sulfonyloxydihydroeugenol derivatives (3a-p). It is proved that the introduction of the acyl group at hydroxy position of dihydroeugenol is more beneficial to improve its anti-oomycete activity than that of the sulfonyl group. These preliminary results will pave the way for further modification of dihydroeugenol in the development of potential new fungicides.

Synthesis, activity, and molecular modeling studies of 1,2,3-triazole derivatives from natural phenylpropanoids as new trypanocidal agents.

The search for compounds with new structural scaffolds is an important tool to the discovery of new drugs against Chagas disease. We report herein the synthesis of 1,2,3-triazoles obtained from eugenol and di-hydroeugenol and their in vitro and in vivo trypanocidal activity. These derivatives were obtained by a three-step objective route and were suitably characterized by 1 H and 13 C nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. Two compounds (9 and 10) showed activity against epimastigote forms of Trypanosoma cruzi (Y strain) in the range 42.8-88.4 µM and were weakly toxic to cardiomyoblast cells (H9c2 cells). The triazole 10 was the most active derivative and could reduce more than 50% of parasitemia after a 100-mg/kg oral treatment of mice infected with T. cruzi. Molecular docking studies suggested this compound could act as a trypanocidal agent by inhibiting cruzain, an essential enzyme for T. cruzi metabolism, usually inhibited by triazole compounds.

Field Trapping Bactrocera latifrons (Diptera: Tephritidae) with Select Eugenol Analogs That Have Been Found to Attract Other 'Non-Responsive' Fruit Fly Species.

Bactrocera latifrons (Hendel) (Diptera: Tephritidae) is a pest fruit fly species native to Oriental Asia which has invaded and established in Hawaii and Tanzania and has been recovered in detection trapping in California. It is largely non-responsive to the male lures cuelure and methyl eugenol. Alpha-ionol + cade oil is a moderately effective male B. latifrons attractant, but is not as attractive as cuelure or methyl eugenol are to other fruit fly species. An improved attractant is therefore desired. With the recent success in finding other non-responsive fruit fly species attracted to isoeugenol, methyl-isoeugenol, or dihydroeugenol in Australia and other countries, we wanted to assess whether B. latifrons might also respond to these “eugenol analogs.” Working with wild B. latifrons populations in Hawaii, we assessed the relative catch of B. latifrons in traps baited with the eugenol analogs with catch in traps baited with alpha-ionol, alpha-ionol + cade oil, or alpha-ionol + eugenol. Catch was significantly higher in traps baited with alpha-ionol + cade oil relative to traps with any of the other baits. There was, though, some male B. latifrons catch in traps baited with dihydroeugenol or isoeugenol but none in traps baited with methyl-isoeugenol.

Synthesis and in vitro evaluation of peracetyl and deacetyl glycosides of eugenol, isoeugenol and dihydroeugenol acting against food-contaminating bacteria.

Essential oils, as well as their separate components, have shown promise as alternatives to synthetic preservatives. Therefore, it would be interesting to optimize the effect of these compounds and to evaluate their applicability as additives in food. To this end, six peracetyl and deacetyl glycosides were synthesized from eugenol, isoeugenol and dihydroeugenol. All of the glycosides were characterized by IR and NMR. The synthesized compounds and their aglycones were evaluated to determine their minimal bactericidal concentrations (MBC) against the spoilage food bacteria Escherichia coli, Listeria monocytogenes, Staphylococcus aureus and Salmonella enteritidis. All deacetyl glycosides were about twice as active as aglycones, and the peracetyl glycosides were, in most cases, equipotent with aglycones. The deacetyl glycoside of dihydroeugenol proved to be the most active compound against the bacteria tested, with a 0.37% MBC v/v for E. coli and 0.18% v/v for the other bacteria.

Effects and mechanisms of eugenol, isoeugenol, coniferylaldehyde and dihydroeugenol on the riboflavin-sensitized photooxidation of α-terpinene in methanol.

The effects of eugenol, isoeugenol, coniferylaldehyde, and dihydroeugenol on the riboflavin-sensitized photooxidation of α-terpinene in methanol were studied. Riboflavin greatly accelerated α-terpinene oxidation in methanol during light illumination, resulting in two major oxidation products (p-cymene and ascaridole). The results clearly showed the involvement of Type I and II mechanisms. All the eugenols exerted strong protective activity on riboflavin sensitized photooxidation of α-terpinene. Dihydroeugenol showed the highest protective activity, followed by isoeugenol, coniferylaldehyde, and eugenol, in a decreasing order. Dihydroeugenol greatly inhibited the production of ascaridole, but showed relatively low inhibitory activity on the formation of p-cymene. The protective activity of dihydroeugenol was higher than those of BHA, BHT and sodium azide. Sodium azide, a specific singlet oxygen quencher, showed strong inhibitory activity on the formation of ascaridole, but very low inhibitory activity on the formation of p-cymene, verifying the feasibility of mechanism study with the present model system.

Ethnobotanical investigations on plants used in folk medicine in the regions of Constantine and Mila (North-East of Algeria).

ETHNO-PHARMACOLOGICAL RELEVANCE: Constantine and Mila regions have been investigated in an ethnobotanical study for the first time. A total of 102 medicinal plants have been cited to treat human ailments. Twenty-eight new species of 31 common plants with 151 new therapeutic applications and 12 new cited species including one endemic specie Zygophyllum cornutum Coss were found as compared to other Algerian regions. In addition, to the best of our knowledge, 369 new medicinal uses of 75 known plants, were reported for the first time in the Mediterranean basin. AIM OF THE STUDY: This study is aimed at contributing to safeguard world cultural heritage and document ethnomedicinal uses of plants in Algeria and the Mediterranean basin; data on the national and global uses in the world were obtained to extract new potential species for further phytochemical and clinical investigations. MATERIALS AND METHODS: The survey was carried out in two cities in the northeast of Algeria: Constantine and Mila. It was based on semi-structured interviews of 79 local informants. Data were analyzed using quantitative indices, namely, informant consensus factor, fidelity level (FL), use value (UV), and relative frequency citation (RFC), to evaluate the reliability and richness of herbal knowledge in the region. RESULTS: The interviewed persons used 102 plant species belonging to 90 genera and distributed among 53 families, represented mainly by Lamiaceae, Apiaceae, and Asteraceae (30%, 13%, and 10%, respectively), which were used to treat 14 ailment categories. The category of most frequent ailments (16%) was digestive disorders (diarrhea, constipation, and stomach bloating). The highest RFC was found for Origanum glandulosum Desf. With regard to the fidelity level, a higher FL was found for Tilia cordata Mill. (100%), followed by Artemisia herba alba Asso. with an FL of 95.74% and Punica granatum L. with an FL of 93.09%) to treat gastrointestinal system diseases, and Aloe sp. L. with an FL of 96.67% for skin diseases. The highest UV was found for Origanum glandulosum Desf. (2.280). Moreover, new medicinal uses were recorded for the first time in Algeria and Mediterranean regions. CONCLUSION: The present study has highlighted the rich herbal knowledge about newfound medicinal plants and their new uses in the Mediterranean region, which could be useful not only in facilitating other studies such as phytochemical and pharmacological investigations and upgrading the sources of biomolecules beneficial to people but also in reopening discussion on pharmacovigilance in herbal medicine as an imperative requirement for local authorities.