Center for Physics of the University of Coimbra

Funder

Organizational Unit

Publications

Unravelling the structure of peroxides with antiparasitic activity: the relative impact of a trioxolane or a tetraoxane pharmacophore on the overall molecular structure

Publication . Amado, Patrícia; Jesus, A. J. Lopes; Paixão, José A.; Fausto, Rui; Cristiano, Maria De Lurdes

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 Hirsh-feld 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 center dot center dot center dot 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 center dot center dot center dot O and C-H center dot center dot center dot pi H-bonds define the molecular packing of 2, while C-H center dot center dot center dot 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.

2022Journal article

Restricted access

Synthesis, structure and antileishmanial evaluation of endoperoxide–pyrazole hybrids

Publication . Amado, Patrícia S. M.; Costa, Inês C. C.; Paixão, José A.; Mendes, Ricardo F.; Cortes, Sofia; Cristiano, Maria L.

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.

2022-08-24Journal article

Open access

Ethyl 7-Acetyl-8a-methyl-3-(1-phenyl-1H-tetrazol-5-yl)-1,4,4a,5,6,8a-hexahydro-7H-pyrano[2,3-c]pyridazine-1-carboxylate

Publication . Lopes, Susana M. M.; Lemos, Americo; Paixão, José A.; Pinho e Melo, Teresa M. V. D.

The Diels–Alder reaction of ethyl 3-(1-phenyl-1H-tetrazol-5-yl-1,2-diaza-1,3-butadiene-1-carboxylate with 2-acetyl-6-methyl-2,3-dihydro-4H-pyran (methyl vinyl ketone dimer) regioselectively afforded the corresponding 3-(tetrazol-5-yl)-hexahydro-7H-pyrano[2,3-c]pyridazine in quantitative yield. An X-ray crystal structure of this cycloadduct is reported.

2022-02-10Journal article

Open access

Synthesis and structure of novel pyrimidine‐thioethers: structural effects on reactivity along with an unpredicted dimethylamination reaction

Publication . Costa, Inês; Frija, Luís M. T.; Augusto, André; Paixão, José A.; Cristiano, Maria de Lurdes

Buchwald–Hartwig reactions have been in the spotlight over the past years due to their usefulness in creating a wide range of chemical skeletons applied in drug discovery. Aminopyrimidines are heterocyclic structures with significant biological relevance and compounds bearing the amino- and diaminopyrimidine motifs have been associated with antiviral, antibacterial, antiparasitic, antifungal, anticancer, and anti-inflammatory properties. Given the notable status of aminopyrimidines in the design of target-specific drug candidates, the synthesis and structure of four aminopyrimidine-arylsulfide conjugates (3, 4, 5, and 6) are reported that are designed to inhibit trypanothione reductase, a key enzyme in the redox pathway of trypanosomatids. When applying the Buchwald–Hartwig synthetic approach, the formation of different products is witnessed by altering the reaction conditions, observing that regioselectivity is conditioned by reaction time and by Boc-protection of the starting 2,6-dichloropyrimidin-4-amine. The electron-withdrawing character of the protecting group appears to increase the susceptibility of the pyrimidine at C2 for further reaction with the solvent, DMF, yielding the corresponding diaminopyrimidine-based conjugates. The crystal structures of the novel aminopyrimidine-arylsulfide conjugate and their Boc-protected 2,6-dichloropyrimidin-4-amine precursors are disclosed and discussed.

2025-08-04Journal article

Restricted access