Infrared vibrational excitation is a promising approach for gaining exceptional control of chemical reactions, in ways that cannot be attained via thermal or electronic excitation. Here, we report an ...unprecedented example of a bond-breaking/bond-forming reaction by vibrational excitation under matrix isolation conditions. Thiotropolone monomers were isolated in cryogenic argon matrices and characterized by infrared spectroscopy and vibrational computations (harmonic and anharmonic). Narrowband near-infrared irradiations tuned at frequencies of first CH stretching overtone (5940 cm–1) or combination modes (5980 cm–1) of the OH tautomer, the sole form of the compound that exists in the as-deposited matrices, led to its conversion into the SH tautomer. The tautomerization in the reverse direction was achieved by vibrational excitation of the SH tautomer with irradiation at 5947 or 5994 cm–1, corresponding to the frequencies of its CH stretching combination and overtone modes. This pioneer demonstration of bidirectional hydroxyl ↔ thiol tautomerization controlled by vibrational excitation creates prospects for new advances in vibrationally induced chemistry.
Okadaic acid (OA) is one of the most potent marine biotoxins, causing diarrheal shellfish poisoning (DSP). The proliferation of microalgae that produce OA and its analogues is frequent, threatening ...human health and socioeconomic development. Several methods have been tested to remove this biotoxin from aquatic systems, yet none has proven enough efficacy to solve the problem. In this work, we synthesized and characterized low-cost composites and tested their efficacy for OA adsorption in saltwater. For the synthesis of the composites, the following starting materials were considered: chitosan of low and medium molecular weight (CH-LW and CH-MW, respectively), activated carbon (AC), and montmorillonite (MMT). Characterization by vibrational spectroscopy (FTIR), X-ray diffraction (XRD), and microscopy revealed differences in the mode of interaction of CH-LW and CH-MW with AC and MMT, suggesting that the interaction of CH-MW with MMT has mainly occurred on the surface of the clay particles and no sufficient intercalation of CH-MW into the MMT interlayers took place. Among the composites tested (CH-LW/AC, CH-MW/AC, CH-MW/AC/MMT, and CH-MW/MMT), CH-MW/MMT was the one that revealed lower OA adsorption efficiency, given the findings evidenced by the structural characterization. On the contrary, the CH-MW/AC composite revealed the highest average percentage of OA adsorption (53 ± 11%). Although preliminary, the results obtained in this work open up good perspectives for the use of this type of composite material as an adsorbent in the removal of OA from marine environments.
Leishmaniases are among the most impacting neglected tropical diseases. In attempts to repurpose antimalarial drugs or candidates, it was found that selected 1,2,4-trioxanes, 1,2,4,5-tetraoxanes, and ...pyrazole-containing chemotypes demonstrated activity against Leishmania parasites. This study reports the synthesis and structure of trioxolane–pyrazole (OZ1, OZ2) and tetraoxane–pyrazole (T1, T2) hybrids obtained from the reaction of 3(5)-aminopyrazole with endoperoxide-containing building blocks. Interestingly, only the endocyclic amine of 3(5)-aminopyrazole was found to act as nucleophile for amide coupling. However, the fate of the reaction was influenced by prototropic tautomerism of the pyrazole heterocycle, yielding 3- and 5-aminopyrazole containing hybrids which were characterized by different techniques, including X-ray crystallography. The compounds were evaluated for in vitro antileishmanial activity against promastigotes of L. tropica and L. infantum, and for cytotoxicity against THP-1 cells. Selected compounds were also evaluated against intramacrophage amastigote forms of L. infantum. Trioxolane–pyrazole hybrids OZ1 and OZ2 exhibited some activity against Leishmania promastigotes, while tetraoxane–pyrazole hybrids proved inactive, most likely due to solubility issues. Eight salt forms, specifically tosylate, mesylate, and hydrochloride salts, were then prepared to improve the solubility of the corresponding peroxide hybrids and were uniformly tested. Biological evaluations in promastigotes showed that the compound OZ1•HCl was the most active against both strains of Leishmania. Such finding was corroborated by the results obtained in assessments of the L. infantum amastigote susceptibility. It is noteworthy that the salt forms of the endoperoxide–pyrazole hybrids displayed a broader spectrum of action, showing activity in both strains of Leishmania. Our preliminary biological findings encourage further optimization of peroxide–pyrazole hybrids to identify a promising antileishmanial lead.
A novel protocol for the preparation of non-symmetrical 1,2,4,5-tetraoxanes and 1,2,4-trioxanes, promoted by the heterogeneous silica sulfuric acid (SSA) catalyst, is reported. Different ketones ...react under mild conditions with gem-dihydroperoxides or peroxysilyl alcohols/β-hydroperoxy alcohols to generate the corresponding endoperoxides in good yields. Our mechanistic proposal, assisted by molecular orbital calculations, at the ωB97XD/def2-TZVPP/PCM(DCM)//B3LYP/6-31G(d) level of theory, enhances the role of SSA in the cyclocondensation step. This novel procedure differs from previously reported methods by using readily available and inexpensive reagents, with recyclable properties, thereby establishing a valid alternative approach for the synthesis of new biologically active endoperoxides.
A chemically diverse range of novel tetraoxanes was synthesized and evaluated in vitro against intramacrophage amastigote forms of
. All 15 tested tetraoxanes displayed activity, with IC
values ...ranging from 2 to 45 µm. The most active tetraoxane, compound LC140, exhibited an IC
value of 2.52 ± 0.65 µm on
intramacrophage amastigotes, with a selectivity index of 13.5. This compound reduced the liver parasite burden of
-infected mice by 37% after an intraperitoneal treatment at 10 mg/kg/day for five consecutive days, whereas miltefosine, an antileishmanial drug in use, reduced it by 66%. These results provide a relevant basis for the development of further tetraoxanes as effective, safe, and cheap drugs against leishmaniasis.
The molecular structure and photochemistry of dispirocyclohexane‐1,3′‐1,2,4,5tetraoxane‐6′,2′′‐tricyclo3.3.1.13,7decan‐4‐one (TX), an antiparasitic 1,2,4,5‐tetraoxane was investigated using matrix ...isolation IR and EPR spectroscopies, together with quantum chemical calculations undertaken at the DFT(B3LYP)/6‐311++G(3df,3pd) level of theory, with and without Grimme's dispersion correction. Photolysis of the matrix‐isolated TX, induced by in situ broadband (λ>235 nm) or narrowband (λ in the range 220–263 nm) irradiation, led to new bands in the infrared spectrum that could be ascribed to two distinct photoproducts, oxepane‐2,5‐dione, and 4‐oxohomoadamantan‐5‐one. Our studies show that these photoproducts result from initial photoinduced cleavage of an O−O bond, with the formation of an oxygen‐centered diradical that regioselectivity rearranges to a more stable (secondary carbon‐centered)/(oxygen‐centered) diradical, yielding the final products. Formation of the diradical species was confirmed by EPR measurements, upon photolysis of the compound at λ=266 nm, in acetonitrile ice (T=10–80 K). Single‐crystal X‐ray diffraction (XRD) studies demonstrated that the TX molecule adopts nearly the same conformation in the crystal and matrix‐isolation conditions, revealing that the intermolecular interactions in the TX crystal are weak. This result is in keeping with observed similarities between the infrared spectrum of the crystalline material and that of matrix‐isolated TX. The detailed structural, vibrational, and photochemical data reported here appear relevant to the practical uses of TX in medicinal chemistry, considering its efficient and broad parasiticidal properties.
Dispirocyclohexane‐1,3′‐1,2,4,5tetraoxane‐6′,2′′‐tricyclo3.3.1.13,7decan‐4‐one, an antiparasitic 1,2,4,5‐tetraoxane, was synthesized and its crystal structure determined by single‐crystal X‐ray diffraction (XRD). Its molecular structure and UV‐induced photochemistry were investigated using matrix isolation IR and EPR spectroscopies together with quantum chemical calculations, undertaken at the DFT(B3LYP)/6‐311++G(3df,3pd) level of theory.
Dispiro-1,2,4-trioxolane, 1, an ozonide with efficient and broad antiparasitic activity, was synthesized and investigated using matrix isolation FTIR and EPR spectroscopies together with both ...B3LYP/6-311++G(3df,3dp) and M06-2X/6-311++G(3df,3dp) theoretical methods. Irradiations (λ ≥ 290 nm) of the matrix isolated 1 (Ar or N2) afforded exclusively 4-oxahomoadamantan-5-one, 4, and 1,4-cyclohexanedione, 5. These results suggested that the reaction proceeded via a dioxygen-centered diradical intermediate, formed upon homolytic cleavage of the labile peroxide bond, which regioselectively isomerized to form the more stable (secondary carbon-centered)/oxygen-centered diradical. In situ EPR measurements during the photolysis of 1 deposited in a MeTHF-matrix led to the detection of signals corresponding to two triplet species, one of which was short-lived while the other proved to be persistent at 10 K. These observations strongly support the proposed mechanism for the photogeneration of 4 and 5, which involves intramolecular rearrangement of the intermediate diradical species 2 to afford the triplet diradical 3.
Leishmaniasis remains one of the ten Neglected Tropical Diseases with significant morbidity and mortality in humans. Current treatment of visceral leishmaniasis is difficult due to a lack of ...effective, non-toxic, and non-extensive medications. This study aimed to evaluate the selectivity of 12 synthetic endoperoxides (1,2,4-trioxolanes; 1,2,4,5-tetraoxanes) and uncover their biochemical effects on
parasites responsible for visceral leishmaniasis. The compounds were screened for in vitro activity against
and
and for cytotoxicity in two monocytic cell lines (J774A.1 and THP-1) using the methyl thiazol tetrazolium assay. Reactive oxygen species formation, apoptosis, and mitochondrial impairment were measured by flow cytometry. The compounds exhibited fair to moderate anti-proliferative activity against promastigotes of the 2
species, with IC
values ranging from 13.0 ± 1.7 µM to 793.0 ± 37.2 µM. Tetraoxanes LC132 and LC138 demonstrated good leishmanicidal activity on
amastigotes (IC
13.2 ± 5.2 and 23.9 ± 2.7 µM) with low cytotoxicity in mammalian cells (SIs 22.1 and 118.6), indicating selectivity towards the parasite. Furthermore, LC138 was able to induce late apoptosis and dose-dependent oxidative stress without affecting mithocondria. Compounds LC132 and LC138 can be further explored as potential antileishmanial chemotypes.
Plasmodium falciparum artemisinin‐resistance boosted the quest for novel plasmodial “fast killers,” uncovering antimalarial candidates OZ439 and E209, whose peroxide precursors are 1,2,4‐trioxolane ...(1) and 1,2,4,5‐tetraoxane (2), differing solely in the pharmacophore (trioxolane or tetraoxane). Combining X‐ray crystallography and vibrational spectroscopy, along with Hirshfeld surface analysis and calculations (CE‐B3LYP/6‐31G(d,p)) of pairwise interaction energies of intermolecular contacts existing in the crystal structure, may deepen the understanding of relative reactivity and properties of these endoperoxides classes. In the crystal, the tetraoxane ring in 2 and the trioxolane‐adamantyl fragment in 1 are disordered, with molecules 1 and 2 existing as two distinct, stable conformations. Whereas the dominant C−H⋅⋅⋅O H‐bonds in 1 connect an adamantyl C−H and O1 or O2 of the trioxolane ring, in 2 they involve the carbonyl oxygen, acting as a double acceptor from phenyl ring C−H groups. C−H⋅⋅⋅O and C−H⋅⋅⋅π H‐bonds define the molecular packing of 2, while C−H⋅⋅⋅H−C van der Waals interactions determine the packing of 1. The dispersive component dominates the interaction energies calculated for the most representative molecular pairs.
The peroxides 1,2,4‐trioxolane (1) and 1,2,4,5‐tetraoxane (2) are precursors of the antimalarial candidates OZ439 and E209, differing only in their pharmacophore (trioxolane or tetraoxane). By combining X‐ray crystallography and vibrational spectroscopy, with Hirshfeld surface analysis and calculations (CE‐B3LYP/6‐31G(d,p)) of pairwise interaction energies of intermolecular contacts existing in the crystal structure, we increased the knowledge regarding their structural features, for a better understanding of the relative reactivity and properties of these endoperoxide classes.
The accumulation of marine biotoxins in shellfish and their consumption causes serious food safety problems, threatening human health and compromising the availability of protein-based food. It is ...thus urgent to develop methodologies for the detoxification of live bivalves, avoiding their economic and nutritional devaluation. In this context, we tested an adsorption mechanism of paralytic shellfish toxins (PST) based on a cation-exchange resin. The first studies using cultures of
(natural producers of PST) showed a decrease of about 80% in overall toxicity after 48 h. Interestingly, we found that the toxins are adsorbed differently, with toxins' structural features playing a part in the adsorption capacity via steric hindrance, electronic effects, or the extent of positive charge density (e.g., dcSTX). The positive effect of the resin in accelerating PST clearance from live mussels (
) is not evident when compared to resin-free clearance; nevertheless, relevant information could be gathered that will facilitate further in vivo studies. Several factors appear to be at play, namely the competition of natural substances (e.g., salts, organic matter) for the same binding sites, the blocking of pores due to interactions between molecules, and/or difficulties in resin absorption by mussels. Additionally, the present work revealed the ability of mussels to neutralize pH and proposes bioconversion reactions among the PST molecules.
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