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.

Discovery of a new dihydroeugenol-chalcone hybrid with cytotoxic and anti-migratory potential: A dual-action hit for cancer therapeutics.

Cancer still represents a serious public health problem and one of the main problems related to the worsening of this disease is the ability of some tumors to develop metastasis. In this work, we synthesized a new series of chalcones and isoxazoles derived from eugenol and analogues as molecular hybrids and these compounds were evaluated against different tumor cell lines. This structural pattern was designed considering the cytotoxic potential already known for eugenol, chalcones and isoxazoles. Notably, chalcones 7, 9, 10, and 11 displayed significant activity (4.2-14.5 µM) against two cancer cell lines, surpassing the potency of the control drug doxorubicin. The reaction of chalcones with hydroxylamine hydrochloride provided the corresponding isoxazoles that were inactive against these cancer cells. The dihydroeugenol chalcone 7 showed the most promising results, demonstrating higher potency against HepG2 (CC50: 4.2 µM) and TOV-21G (CC50: 7.2 µM). Chalcone 7 was also three times less toxic than doxorubicin considering HepG2 cells, with a selectivity index greater than 11. Further investigations including clonogenic survival, cell cycle progression and cell migration assays confirmed the compelling antitumoral potential of chalcone 7, as it reduced long-term survival due to DNA fragmentation, inducing cell death and inhibiting HepG2 cells migration. Moreover, in silico studies involving docking and molecular dynamics revealed a consistent binding mode of chalcone 7 with metalloproteinases, particularly MMP-9, shedding light on its potential mechanism of action related to anti-migratory effects. These significant findings suggest the inclusion of compound 7 as a promising candidate for future studies in the field of cancer therapeutics.

Combining eugenol and dihydroeugenol with a piperazine moiety to create new antimicrobial agents that are effective against resistant species.

Historically, the piperazine moiety has been demonstrated to possess pharmacophoric properties, and has subsequently been incorporated in many drugs that have antitumor, antimalarial, antiviral, antibacterial and antifungal properties. Derivatives of eugenol and dihydroeugenol have also been reported as being bioactive compounds. This study reports the synthesis of a range of eugenol/dihydroeugenol - piperazine derivatives which have been tested as antimicrobial compounds against Gram positive, Gram negative and rapid-growing mycobacteria (RGM). The rationale employed in the design of the structural pattern of these new derivatives, provides useful insights into the structure-activity relationships (SAR) of the series. Antimicrobial activity tests were extremely encouraging, with the majority of the synthesised compounds being more active than eugenol and dihydroeugenol starting materials. The antimicrobial potential was most notable against the Gram-negative species K. pneumoniae and P. aeruginosa, but there was also significant performance against the Gram-positive strains S. epidermidis and S. aureus and the Rapidly Growing Mycobacteria (RGM) strains tested. Tests using the synthesised compounds against multidrug-resistance clinical (MDR) isolates also showed high activity. The biofilm inhibition tests using M. fortuitum showed that all evaluated derivatives were able to inhibit biofilm formation even at low concentrations. In terms of structural-activity relationships; the results generated by this study demonstrate that the compounds with bulky substituents on the piperazine subunit were much more active than those with less bulky groups, or no groups. Importantly, the derivatives with a sulfonamide side chain were the most potent compounds. A further observation was that those compounds with a para-substituted benzenesulfonamide ring stand out, regardless of whether this substituent is a donor or an electron-withdrawing group.

Evaluation of antiplasmodial activity in silico and in vitro of N-acylhydrazone derivatives.

N-acylhydrazones are considered privileged structures in medicinal chemistry, being part of antimicrobial compounds (for example). In this study we show the activity of N-acylhydrazone compounds, namely AH1, AH2, AH4, AH5 in in vitro tests against the chloroquine-resistant strain of Plasmodium falciparum (W2) and against WI26 VA-4 human cell lines. All compounds showed low cytotoxicity (LC50 > 100 µM). The AH5 compound was the most active against Plasmodium falciparum, with an IC50 value of 0.07 µM. AH4 and AH5 were selected among the tested compounds for molecular docking calculations to elucidate possible targets involved in their mechanism of action and the SwissADME analysis to predict their pharmacokinetic profile. The AH5 compound showed affinity for 12 targets with low selectivity, while the AH4 compound had greater affinity for only one target (3PHC). These compounds met Lipinski's standards in the ADME in silico tests, indicating good bioavailability results. These results demonstrate that these N-acylhydrazone compounds are good candidates for future preclinical studies against malaria.

Synthesis of eugenol-derived glucosides and evaluation of their ability in inhibiting the angiotensin converting enzyme.

We report here a series of glucosides which are active as inhibitors of the angiotensin converting enzyme (ACE). They are structurally related to the natural compound eugenol and exhibited significant inhibition values. Their syntheses were expeditious and we could obtain informative docking plots of them complexed to this enzyme. A glucoside derived from eugenol, carrying a carboxylic group in the aglycone, was the most active of them (with an IC50 of 0.4 mM) and showed good binding energies in docking studies with ACE. Moreover, computational prediction of toxicity risks, physicochemical properties and drug score show that the glucoside derivative of eugenol is a suitable compound for optimisation studies aimed at finding new drug candidates.

Synthesis of New Hybrid Derivatives from Metronidazole and Eugenol Analogues as Trypanocidal Agents.

BACKGROUND: The search for new drug compounds is always challenging and there are several different strategies that involve the most varied and creative approaches in medicinal chemistry. One of them is the technique of molecular hybridisation: forming a hybrid compound from two or more pharmacophoric subunits. These hybrids may maintain the characteristics of the original compound and preferably show improvements to its pharmacological action, with reduced side effects and lower toxicity when compared to the original components. This study specifically focuses on synthesising hybrid molecules which demonstrate trypanocidal activity against the epimastigote and trypomastigote forms of Trypanosoma cruzi. METHODS: In this context, this study centres on the synthesis of a novel structural scaffold via molecular hybridisation; by using a triazole species to link a metronidazole unit to a eugenol analogue unit, the objective being to combine their therapeutic properties into a new molecular structure. The resulting hybrid molecules were evaluated against T. cruzi which is responsible for high incidences of trypanosomiasis in tropical countries such as Brazil. RESULTS: The results of this study showed an improvement in the anti-parasitic activity of the hybrid compounds with the best result coming from hybrid compounds [8] and [9], which present an activity similar to the control drug benznidazole. The new compounds, utilising a triazole species as a coupling connector, demonstrated promising results and has highlighted the path for planning similar structural patterns to investigate new compounds. CONCLUSIONS: In summary, we can conclude that the synthesised hybrid compounds demonstrate that using a triazole to link metronidazole with natural phenols, produces hybrid molecules that are promising as a new class of compounds of therapeutic interest for further investigation.