Formation and Stability of Benzylic Amide [2]- and [3]Rotaxanes: an Intercomponent Interactions Study.

One of the most recent focuses in supramolecular chemistry is developing molecules designed to exhibit programmable properties at the molecular level. Rotaxanes, which function as molecular machines with movements controlled by external stimuli, are prime candidates for this purpose. However, the controlled synthesis of rotaxanes, especially amide-benzylic rotaxanes with more than two components, remains an area ripe for exploration. In this study, we aim to elucidate the formation of amide-benzylic [3]rotaxanes using a thread that includes a conventional succinamide station and an innovative triazole-carbonyl station. Including the triazole-carbonyl station introduces new perspectives into the chemistry of rotaxanes, influencing their conformation and dynamics. The synthesis of two-station rotaxanes with varying stoppers demonstrated that the macrocycle consistently occupies the succinamide station, providing greater stability as evidenced by NMR and SC-XRD analyses. The presence of a triazole-carbonyl station facilitated the formation of a second macrocycle exclusively when a secondary amide was employed as the stopper group, presumably due to decreased steric hindrance. Moreover, the second macrocycle directly forms at the triazole-carbonyl station. This investigation reveals that slight modifications in the thread structure can dramatically impact the formation, stability, and interactions between components of rotaxanes.

Structure-Aided Computational Design of Triazole-Based Targeted Covalent Inhibitors of Cruzipain.

Cruzipain (CZP), the major cysteine protease present in T. cruzi, the ethiological agent of Chagas disease, has attracted particular attention as a therapeutic target for the development of targeted covalent inhibitors (TCI). The vast chemical space associated with the enormous molecular diversity feasible to explore by means of modern synthetic approaches allows the design of CZP inhibitors capable of exhibiting not only an efficient enzyme inhibition but also an adequate translation to anti-T. cruzi activity. In this work, a computer-aided design strategy was developed to combinatorially construct and screen large libraries of 1,4-disubstituted 1,2,3-triazole analogues, further identifying a selected set of candidates for advancement towards synthetic and biological activity evaluation stages. In this way, a virtual molecular library comprising more than 75 thousand diverse and synthetically feasible analogues was studied by means of molecular docking and molecular dynamic simulations in the search of potential TCI of CZP, guiding the synthetic efforts towards a subset of 48 candidates. These were synthesized by applying a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) centered synthetic scheme, resulting in moderate to good yields and leading to the identification of 12 hits selectively inhibiting CZP activity with IC50 in the low micromolar range. Furthermore, four triazole derivatives showed good anti-T. cruzi inhibition when studied at 50 µM; and Ald-6 excelled for its high antitrypanocidal activity and low cytotoxicity, exhibiting complete in vitro biological activity translation from CZP to T. cruzi. Overall, not only Ald-6 merits further advancement to preclinical in vivo studies, but these findings also shed light on a valuable chemical space where molecular diversity might be explored in the search for efficient triazole-based antichagasic agents.

Design, synthesis, docking studies and bioactivity evaluation of 1,2,3-triazole eugenol derivatives.

Aim: The design, synthesis, docking studies and evaluation of the in vitro antifungal and cytotoxic properties of eugenol (EUG) containing 1,2,3-triazole derivatives are reported. Most of the derivatives have not been reported.Materials & methods: The EUG derivatives were synthesized, molecular docked and tested for their antifungal activity.Results: The compounds showed potent antifungal activity against Trichophyton rubrum, associated with dermatophytosis. Compounds 2a and 2i exhibited promising results, with 2a being four-times more potent than EUG. The binding mode prediction was similar to itraconazole in the lanosterol-14-α-demethylase wild-type and G73E mutant binding sites. Additionally, the pharmacokinetic profile prediction suggests good gastrointestinal absorption and potential oral administration.Conclusion: Compound 2a is a promising antifungal agent against dermatophytosis caused by T. rubrum.

[Box: see text].

Novel tetrahydropyran-triazole hybrids with antiproliferative activity against human tumor cells.

A series of new hybrid compounds was prepared combining tetrahydropyran rings with different aromatic systems by means of a 1,2,3-triazole, using a building block strategy. The design of these structures was guided by Lead-Likeness and Molecular Analysis (LLAMA) software, adding modifications to our most potent scaffold (the tetrahydropyran ring) to generate promising "lead-like" candidates, which were subsequently compared against reported anticancer compounds. Our synthesized compounds demonstrated significant antiproliferative activity when compared with the standards cisplatin and 5-fluorouracil, across a panel of six different tumor cell lines. Moreover, compared with our group's previous hybrid compounds, these new structures exhibit similar activity while offering simpler synthesis and greater potential for structural diversification, a fact that was previously an issue. Further investigations on the most active compounds included assessments of reproductive cell survival, inhibition of cell migration, and effects on nuclear morphology, indicating potential diverse mechanisms of action for these compounds. Pharmacokinetic properties were also calculated for the whole series of compounds using the pkCSM online software.

Mechanistic insights into C(sp2)-H activation in 1-Phenyl-4-vinyl-1H-1,2,3-triazole derivatives: a theoretical study with palladium acetate catalyst.

CONTEXT: The activation of C-H bonds is a fundamental process in synthetic organic chemistry, which enables their replacement by highly reactive functional groups. Coordination compounds serve as effective catalysts for this purpose, as they facilitate chemical transformations by interacting with C-H bonds. A comprehensive understanding of the mechanism of activation of this type of bond lays the foundation for the development of efficient protocols for cross-coupling reactions. We explored the activation of C(sp2)-H bonds in 1-Phenyl-4-vinyl-1H-1,2,3-triazole derivatives with CH3, OCH3, and NO2 substituents in the para position of the phenyl ring, using palladium acetate as catalyst. The studied reaction is the first step for subsequent conjugation of the triazoles with naphthoquinones in a Heck-type reaction to create a C-C bond. The basic nitrogen atoms of the 1,2,3-triazole coordinate preferentially with the cationic palladium center to form an activated species. A concerted proton transfer from the terminal vinyl carbon to one of the acetate ligands with low activation energy is the main step for the C(sp2)-H activation. This study offers significant mechanistic insights for enhancing the effectiveness of C(sp2)-H activation protocols in organic synthesis. METHODS: All calculations were performed using the Gaussian 09 software package and density functional theory (DFT). The structures of all reaction path components were fully optimized using the CAM-B3LYP functional with the Def2-SVP basis set. The optimized geometries were analyzed by computing the second-order Hessian matrix to confirm that the corresponding minimum or transition state was located. To account for solvent effects, the Polarizable Continuum Model of the Integral Equation Formalism (IEFPCM) with water as the solvent was used.

Design and Synthesis of Eugenol Derivatives Bearing a 1,2,3-Triazole Moiety for Papaya Protection against Colletotrichum gloeosporioides.

A series of 19 novel eugenol derivatives containing a 1,2,3-triazole moiety was synthesized via a two-step process, with the key step being a copper(I)-catalyzed azide-alkyne cycloaddition reaction. The compounds were assessed for their antifungal activities against Colletotrichum gloeosporioides, the causative agent of papaya anthracnose. Triazoles 2k, 2m, 2l, and 2n, at 100 ppm, were the most effective, reducing mycelial growth by 88.3, 85.5, 82.4, and 81.4%, respectively. Molecular docking calculations allowed us to elucidate the binding mode of these derivatives in the catalytic pocket of C. gloeosporioides CYP51. The best-docked compounds bind closely to the heme cofactor and within the channel access of the lanosterol (LAN) substrate, with crucial interactions involving residues Tyr102, Ile355, Met485, and Phe486. From such studies, the antifungal activity is likely attributed to the prevention of substrate LAN entry by the 1,2,3-triazole derivatives. The triazoles derived from natural eugenol represent a novel lead in the search for environmentally safe agents for controlling C. gloeosporioides.

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.

New thymol-derived triazole exhibits promising activity against Trichophyton rubrum.

Fungal infections have emerged worldwide, and azole antifungals are widely used to control these infections. However, the emergence of antifungal resistance has been compromising the effectiveness of these drugs. Therefore, the objective of this study was to evaluate the antifungal and cytotoxic activities of the nine new 1,2,3 triazole compounds derived from thymol that were synthesized through Click chemistry. The binding mode prediction was carried out by docking studies using the crystallographic structure of Lanosterol 14α-demethylase G73E mutant from Saccharomyces cerevisiae. The new compounds showed potent antifungal activity against Trichophyton rubrum but did not show relevant action against Aspergillus fumigatus and Candida albicans. For T. rubrum, molecules nº 5 and 8 showed promising results, emphasizing nº 8, whose fungicidal and fungistatic effects were similar to fluconazole. In addition, molecule nº 8 showed low toxicity for keratinocytes and fibroblasts, concluding that this compound demonstrates promising characteristics for developing a new drug for dermatophytosis caused by T. rubrum, or serves as a structural basis for further research.

Highly crystalline and fluorescent BODIPY-labelled phenyl-triazole-coumarins as n-type semiconducting materials for OFET devices.

In this work, the synthesis of BODIPY-phenyl-triazole labelled coumarins (BPhTCs) using a two-step approach is described. The influence of the BODIPY appending on the photophysical, electrochemical and thermal properties of the phenyl-triazole-coumarin precursors (PhTCs) was investigated. Band gap energies were measured by absorption spectroscopy (2.20 ± 0.02 eV in the solid and 2.35 ± 0.01 eV in solution) and cyclic voltammetry (2.10 ± 0.05 eV). The results are supported by DFT calculations confirming the presence of lowest LUMO levels that facilitate the electron injection and stabilize the electron transport. Their charge-transport parameters were measured in Organic Field-Effect Transistor (OFET) devices. BPhTCs showed an ambipolar transistor behavior with good n-type charge mobilities (10-2 cm2V-1s-1) allowing these derivatives to be employed as promising semiconducting crystalline and fluorescent materials with good thermal and air stability up to 250 °C.

New azaaurone derivatives as potential multitarget agents in HIV-TB coinfection.

Tuberculosis (TB) disease, caused by Mycobacterium tuberculosis (Mtb) is the leading cause of death among people with human immunodeficiency virus (HIV) infection. No dual-target drug is currently being used to simultaneously treat both infections. This work aimed to obtain new multitarget HIV-TB agents, with the goal of optimizing treatments and preventing this coinfection. These compounds incorporate the structural features of azaaurones as anti-Mtb and zidovudine (AZT) as the antiretroviral moiety. The azaaurone scaffold displayed submicromolar activities against Mtb, and AZT is a potent antiretroviral drug. Six derivatives were synthetically generated, and five were evaluated against both infective agents. Evaluations of anti-HIV activity were carried out in HIV-1-infected MT-4 cells and on endogenous HIV-1 reverse transcriptase (RT) activity. The H37Rv strain was used for anti-Mtb assessments. Most compounds displayed potent antitubercular and moderate anti-HIV activity. (E)-12 exhibited a promising multitarget profile with an MIC90 of 2.82 µM and an IC50 of 1.98 µM in HIV-1-infected T lymphocyte cells, with an 84% inhibition of RT activity. Therefore, (E)-12 could be the first promising compound from a family of multitarget agents used to treat HIV-TB coinfection. In addition, the compound could offer a prototype for the development of new strategies in scientific research to treat this global health issue.

Leishmanicidal activity and 4D quantitative structure-activity relationship and molecular docking studies of vanillin-containing 1,2,3-triazole derivatives.

Aim: The assessment of the antileishmanial potential of 22 vanillin-containing 1,2,3-triazole derivatives against Leishmania braziliensis is reported. Materials & methods: Initial screening was performed against the parasite promastigote form. The most active compound, 4b, targeted parasites within amastigotes (IC50 = 4.2 ± 1.0 µmol l-1), presenting low cytotoxicity and a selective index value of 39. 4D quantitative structure-activity relationship and molecular docking studies provided insights into structure-activity and biological effects. Conclusion: A vanillin derivative with significant antileishmanial activity was identified. Enhanced activity was linked to increased electrostatic and Van der Waals interactions near the benzyl ring of the derivatives. Molecular docking indicated the inhibition of the Leishmania amazonensis sterol 14α-demethylase, using Leishmania infantum sterol 14α-demethylase as a model, without affecting the human isoform. Inhibition was active site competition with lanosterol.

Antiviral evaluation of 1,4-disubstituted-1,2,3-triazole derivatives against Chikungunya virus.

Aim: This work aimed to investigate the antiviral activity of two 1,4-disubstituted-1,2,3-triazole derivatives (1 and 2) against Chikungunya virus (CHIKV) replication. Materials & methods: Cytotoxicity was analyzed using colorimetric assays and the antiviral potential was evaluated using plaque assays and computational tools. Results: Compound 2 showed antiviral activity against CHIKV 181-25 in BHK-21 and Vero cells. Also, this compound presented a higher activity against CHIKV BRA/RJ/18 in Vero cells, like compound 1. Compound 2 exhibited virucidal activity and inhibited virus entry while compound 1 inhibited virus release. Molecular docking suggested that these derivatives inhibit nsP1 protein while compound 1 may also target capsid protein. Conclusion: Both compounds exhibit promising antiviral activity against CHIKV by blocking different steps of virus replication.

Anti-Trypanosoma cruzi Activity, Mutagenicity, Hepatocytotoxicity and Nitroreductase Enzyme Evaluation of 3-Nitrotriazole, 2-Nitroimidazole and Triazole Derivatives.

Chagas disease (CD), which is caused by Trypanosoma cruzi and was discovered more than 100 years ago, remains the leading cause of death from parasitic diseases in the Americas. As a curative treatment is only available for the acute phase of CD, the search for new therapeutic options is urgent. In this study, nitroazole and azole compounds were synthesized and underwent molecular modeling, anti-T. cruzi evaluations and nitroreductase enzymatic assays. The compounds were designed as possible inhibitors of ergosterol biosynthesis and/or as substrates of nitroreductase enzymes. The in vitro evaluation against T. cruzi clearly showed that nitrotriazole compounds are significantly more potent than nitroimidazoles and triazoles. When their carbonyls were reduced to hydroxyl groups, the compounds showed a significant increase in activity. In addition, these substances showed potential for action via nitroreductase activation, as the substances were metabolized at higher rates than benznidazole (BZN), a reference drug against CD. Among the compounds, 1-(2,4-difluorophenyl)-2-(3-nitro-1H-1,2,4-triazol-1-yl)ethanol (8) is the most potent and selective of the series, with an IC50 of 0.39 µM and selectivity index of 3077; compared to BZN, 8 is 4-fold more potent and 2-fold more selective. Moreover, this compound was not mutagenic at any of the concentrations evaluated, exhibited a favorable in silico ADMET profile and showed a low potential for hepatotoxicity, as evidenced by the high values of CC50 in HepG2 cells. Furthermore, compared to BZN, derivative 8 showed a higher rate of conversion by nitroreductase and was metabolized three times more quickly when both compounds were tested at a concentration of 50 µM. The results obtained by the enzymatic evaluation and molecular docking studies suggest that, as planned, nitroazole derivatives may utilize the nitroreductase metabolism pathway as their main mechanism of action against Trypanosoma cruzi. In summary, we have successfully identified and characterized new nitrotriazole analogs, demonstrating their potential as promising candidates for the development of Chagas disease drug candidates that function via nitroreductase activation, are considerably selective and show no mutagenic potential.

Antitrypanosomal Activity of 1,2,3-Triazole-Based Hybrids Evaluated Using In Vitro Preclinical Translational Models.

Chagas disease therapy still relies on two nitroderivatives, nifurtimox and benznidazole (Bz), which have important limitations and serious adverse effects. New therapeutic alternatives for this silent disease, which has become a worldwide public health problem, are essential for its control and elimination. In this study, 1,2,3-triazole analogues were evaluated for efficacy against T. cruzi. Three triazole derivatives, 1d (0.21 µM), 1f (1.23 µM), and 1g (2.28 µM), showed potent activity against trypomastigotes, reaching IC50 values 10 to 100 times greater than Bz (22.79 µM). Promising candidates are active against intracellular amastigotes (IC50 ≤ 6.20 µM). Treatment of 3D cardiac spheroids, a translational in vitro model, significantly reduced parasite load, indicating good drug diffusion and efficacy. Oral bioavailability was predicted for triazole derivatives. Although infection was significantly reduced without drug pressure in a washout assay, the triazole derivatives did not inhibit parasite resurgence. An isobologram analysis revealed an additive interaction when 1,2,3-triazole analogs and Bz were combined in vitro. These data indicate a strengthened potential of the triazole scaffold and encourage optimization based on an analysis of the structure-activity relationship aimed at identifying new compounds potentially active against T. cruzi.

A Novel MDM2-Binding Chalcone Induces Apoptosis of Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) represents ~90% of all oral cancers, being the eighth most common cancer in men. The overall 5-year survival rate is only 39% for metastatic cancers, and currently used chemotherapeutics can cause important side effects. Thus, there is an urgency in developing new and effective anti-cancer agents. As both chalcones and 1,2,3-triazoles are valuable pharmacophores/privileged structures in the search for anticancer compounds, in this work, new 1,2,3-triazole-chalcone hybrids were synthesized and evaluated against oral squamous cell carcinoma. By using different in silico, in vitro, and in vivo approaches, we demonstrated that compound 1f has great cytotoxicity and selectivity against OSCC (higher than carboplatin and doxorubicin) and other cancer cells in addition to showing minimal toxicity in mice. Furthermore, we demonstrate that induced cell death occurs by apoptosis and cell cycle arrest at the G2/M phase. Moreover, we found that 1f has a potential affinity for MDM2 protein, similar to the known ligand nutlin-3, and presents a better selectivity, pharmacological profile, and potential to be orally absorbed and is not a substrate of Pg-P when compared to nutlin-3. Therefore, we conclude that 1f is a good lead for a new chemotherapeutic drug against OSCC and possibly other types of cancers.

Biological activity of 1,2,3-triazole-2-amino-1,4-naphthoquinone derivatives and their evaluation as therapeutic strategy for malaria control.

Malaria can be caused by several Plasmodium species and the development of an effective vaccine is challenging. Currently, the most effective tool to control the disease is the administration of specific chemotherapy; however, resistance to the frontline antimalarials is one of the major problems in malaria control and thus the development of new drugs becomes urgent. The study presented here sought to evaluate the antimalarial activities of compounds derived from 2-amino-1,4-naphthoquinones containing 1,2,3-triazole using in vivo and in vitro models. 1H-1,2,3-Triazole 2-amino-1,4-naphthoquinone derivatives were synthesized and evaluated for antimalarial activity in vitro, using P. falciparum W2 chloroquine (CQ) resistant strain and in vivo using the murine-P. berghei ANKA strain. Acute toxicity was determined as established by the OECD (2001). Cytotoxicity was evaluated against HepG2 and Vero mammalian cell lines. Transmission electron microscopy of the Plasmodium falciparum trophozoite (early and late stages) was used to evaluate the action of compounds derived at ultra-structural level. The compounds displayed low cytotoxicity CC50 > 100 µM, neither did they cause hemolysis at the tested doses and nor the signs of toxicity in the in vivo acute toxicity test. Among the five compounds tested, one showed IC50 values in submicromolar range of 0.8 µM. Compounds 7, 8 and 11 showed IC50 values < 5 µM, and selectivity index (SI) ranging from 6.8 to 343 for HepG2, and from 13.7 to 494.8 for Vero cells. Compounds 8 and 11 were partially active against P. berghei induced parasitemia in vivo. Analysis of the ultrastructural changes associated with the treatment of these two compounds, showed trophozoites with completely degraded cytoplasm, loss of membrane integrity, organelles in the decomposition stage and possible food vacuole deterioration. Our results indicated that compounds 8 and 11 may be considered hit molecules for antimalarial drug discovery platform and deserve further optimization studies.

Synthesis and Fungicide Activity on Asperisporium caricae of Glycerol Derivatives Bearing 1,2,3-Triazole Fragments.

In agriculture, the control of fungal infections is essential to improve crop quality and productivity. This study describes the preparation and fungicidal activity evaluation of 12 glycerol derivatives bearing 1,2,3-triazole fragments. The derivatives were prepared from glycerol in four steps. The key step corresponded to the Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC) click reaction between the azide 4-(azidomethyl)-2,2-dimethyl-1,3-dioxolane (3) and different terminal alkynes (57-91% yield). The compounds were characterized by infrared spectroscopy, nuclear magnetic resonance (1H and 13C), and high-resolution mass spectrometry. The in vitro assessment of the compounds on Asperisporium caricae, that is, the etiological agent of papaya black spot, at 750 mg L-1 showed that the glycerol derivatives significantly inhibited conidial germination with different degrees of efficacy. The most active compound 4-(3-chlorophenyl)-1-((2,2-dimethyl-1,3-dioxolan-4-yl) methyl)-1H-1,2,3-triazole (4c) presented a 91.92% inhibition. In vivo assays revealed that 4c reduced the final severity (70.7%) and area under the disease severity progress curve of black spots on papaya fruits 10 days after inoculation. The glycerol-bearing 1,2,3-triazole derivatives also present agrochemical-likeness properties. Our in silico study using molecular docking calculations show that all triazole derivatives bind favorably to the sterol 14α-demethylase (CYP51) active site at the same region of the substrate lanosterol (LAN) and fungicide propiconazole (PRO). Thus, the mechanism of action of the compounds 4a-4l may be the same as the fungicide PRO, blocking the entrance/approximation of the LAN into the CYP51 active site by steric effects. The reported results point to the fact that the glycerol derivatives may represent a scaffold to be explored for the development of new chemical agents to control papaya black spot.

Effective enantioselective recognition by steady-state fluorescence spectroscopy: Towards a paradigm shift to optical sensors with unusual chemical architecture.

A series of amino acid-derived 1,2,3-triazoles presenting the amino acid residue and the benzazole fluorophore connected by a triazole-4-carboxylate spacer was studied for enantioselective recognition using only steady-state fluorescence spectroscopy in solution. In this investigation, the optical sensing was performed with D-(-) and L-(+)-Arabinose and (R)-(-) and (S)-(+)-Mandelic acid as chiral analytes. The optical sensors showed specific interactions with each pair of enantiomers, allowing photophysical responses, which were used for their enantioselective recognition. DFT calculations confirm the specific interaction between the fluorophores and the analytes corroborating the observed high enantioselectivity of these compounds with the studied enantiomers. Finally, this study investigated nontrivial sensors for chiral molecules by a mechanism different than turn-on fluorescence and has the potential to broad chiral compounds with fluorophoric units as optical sensors for enantioselective sensing.

Synthesis of vanillin derivatives with 1,2,3-triazole fragments and evaluation of their fungicide and fungistatic activities.

Vanillin is the main component of natural vanilla extract and is responsible for its flavoring properties. Besides its well-known applications as an additive in food and cosmetics, it has also been reported that vanillin can inhibit fungi of clinical interest, such as Candida spp., Cryptococcus spp., Aspergillus spp., as well as dermatophytes. Thus, the present work approaches the synthesis of a series of vanillin derivatives with 1,2,3-triazole fragments and the evaluation of their antifungal activities against Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, Cryptococcus gattii, Trichophyton rubrum, and Trichophyton interdigitale strains. Twenty-two vanillin derivatives were obtained, with yields in the range of 60%-91%, from copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) click reaction between two terminal alkynes prepared from vanillin and different benzyl azides. In general, the evaluated compounds showed moderate activity against the microorganisms tested, with minimum inhibitory concentration (MIC) values ranging from 32 to >512 µg mL-1 . Except for compound 3b against the C. gattii R265 strain, all vanillin derivatives showed fungicidal activity for the yeasts tested. The predicted physicochemical and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties for the compounds indicated favorable profiles for drug development. In addition, a four-dimensional structure-activity relationship (4D-SAR) analysis was carried out and provided useful insights concerning the structures of the compounds and their biological profile. Finally, molecular docking calculations showed that all compounds bind favorably at the lanosterol 14α-demethylase enzyme active site with binding energies ranging from -9.1 to -12.2 kcal/mol.

Synthesis and virucide activity on zika virus of 1,2,3-triazole-containing vanillin derivatives.

The Zika virus (ZIKV) is an arbovirus and belongs to the Flaviviridae family and Flavivirus genus, with dissemination in the Americas. In Brazil, the predominant strain is the Asian, promoting outbreaks that started in 2015 and are directly related to microcephaly in newborns and Guillain-Barré syndrome in adults. Recently, researchers identified a new African strain circulating in Brazil at the mid-end of 2018 and the beginning of 2019, with the potential to originate a new epidemic. To date, there is no approved vaccine or drug for the treatment of Zika syndrome, and the development of therapeutic alternatives to treat it is of relevance. A critical approach is to use natural products when searching for new chemical agents to treat Zika syndrome. The present investigation describes the preparation of a series of 1,2,3-triazoles derived from the natural product vanillin and the evaluation of their virucide activity. A series of fourteen derivatives were prepared via alkylation of vanillin followed by CuAAC (the copper(I)-catalyzed azide-alkyne cycloaddition) reaction. The compounds were fully characterized by infrared (I.R.), nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HRMS) techniques. The cytotoxicity of Vero cells and the effect on the Zika Virus of the vanillin derivatives were evaluated. It was found that the most effective compound corresponded to 4-((1-(4-isopropylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-methoxybenzaldehyde (8) (EC50 = 27.14 µM, IC50 = 334.9 µM). Subsequent assessments, namely pre and post-treatment assays, internalization and adsorption inhibition assays, kinetic, electronic microscopy analyses, and zeta potential determination, revealed that compound 8 blocks the Zika virus infection in vitro by acting on the viral particle. A molecular docking study was performed, and the results are also discussed.