Development of pyrazolopyrimidines as anti-tuberculosis agents – hit-to-lead optimization and chemical proteomic target identification.

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Publications

Structure and IR Spectra of 3(5)-Aminopyrazoles and UV-induced tautomerization in argon matrix

Publication . Secrieru, Alina; Lopes, Susy; Cristiano, Maria L. S.; Fausto, Rui

The prototropic tautomerism in 3(5)-aminopyrazoles was investigated by matrix isolation infrared (IR) spectroscopy, supported by DFT(B3LYP)/6-311++G(d,p) calculations. In consonance with the experimental data, the calculations predict tautomer 3-aminopyrazole (3AP) to be more stable than the 5-aminopyrazole (5AP) tautomer (calculated energy difference: 10.7 kJ mol−1 ; Gibbs free energy difference: 9.8 kJ mol−1 ). The obtained matrix isolation IR spectra (in both argon and xenon matrices) were interpreted, and the observed bands were assigned to the tautomeric forms with help of vibrational calculations carried out at both harmonic and anharmonic levels. The matrix-isolated compound (in argon matrix) was then subjected to in situ broadband UV irradiation (λ > 235 nm), and the UV-induced transformations were followed by IR spectroscopy. Phototautomerization of the 3AP tautomer into the 5AP form was observed as the strongly prevalent reaction.

2021-07-15Journal article

Open access

4-hydroxyquinolin-2(1H)-one isolated in cryogenic argon and xenon matrices: tautomers and photochemistry

Publication . Secrieru, Alina; Lopes, S.; Nikitin, T.; Cristiano, Maria de Lurdes; Fausto, R.

4-Hydroxyquinolin-2(1H)-one (4HQ2O) was synthesized, isolated in cryogenic matrices (argon and xenon), and studied by infrared spectroscopy. Quantum chemical calculations carried out at the DFT(B3LYP)/6-311++G (3df,3pd) level of theory were used to determine the conformational and tautomeric properties of the molecule. Two tautomeric forms were identified in the as-deposited matrices with the help of the theoretical data. To investigate the photochemistry of the compound, in situ broadband ultraviolet (lambda > 283 nm) irradiation of the asdeposited argon matrix was performed. This irradiation led to the generation of an additional tautomer, together with the products of fragmentation of the heterocyclic ring of the molecule, specifically isocyanic acid and carbon monoxide. Photoproducts such as 1,3-dihydro-2H-indol-2-one and cyclohepta-1,2,4,6-tetraene were also observed in the photolyzed argon matrix. A comprehensive assignment of the infrared spectra of all the species observed experimentally is presented.

2024-09Journal article

Open access

Development of novel antitubercular agents: design, synthesis, in vitro evaluation and in silico studies

Publication . Secrieru, Alina; Cristiano, Maria de Lurdes dos Santos; O’Neill, Paul Michael

Tuberculosis remains a significant global health threat, with millions of new cases and deaths reported annually. The emergence and spread of drug-resistant TB strains pose a major challenge, highlighting the critical need for novel antitubercular agents. This doctoral program investigated the potential of three promising heterocyclic compound classes for their antitubercular activity: fluoroquinolones, benzothiazinones, and pyrazolopyrimidines. A series of delafloxacin analogues substituted at the C-7 position were synthesised and evaluated for their antimycobacterial activity. The synthetic approach to the compounds was optimised, emphasising the relevance of a careful selection of cyclic amines for substitution at the C-7 position. Biological assays identified a hit compound, AS-2-13, with exceptional activity (IC50 = 0.041 μM). In silico docking studies suggested common interactions between most analogs and the gyrase target, with some compounds exhibiting additional interactions with DNA chains or hydrophobic interactions with protein residues. This study also explored benzothiazinones that could target DprE1 non-covalently, a critical protein in Mycobacterium tuberculosis. We synthesised nine new analogues and evaluated their activity. While promising, the non-covalent compounds displayed significantly lower activity than their covalent counterparts. Molecular modelling studies suggest a distinct binding orientation within the DprE1 active site for the non-covalent series, potentially hindering interaction with crucial residues and explaining the reduced activity. Lastly, we investigated pyrazolo[1,5-a]pyrimidines as potential candidates for anti-tuberculosis therapy. A common synthetic method utilises 3-aminopyrazole, but tautomerism can complicate the reaction. To address this challenge, we examined the factors influencing tautomerism in 3(5)-aminopyrazole with the goal of developing methods for selective synthesis. Subsequently, employing a combination of experimental and theoretical techniques, the structure and stability of 3-aminopyrazole and 5-aminopyrazole tautomers was analysed, revealing that 3-aminopyrazole is the most stable form and dominates in cryogenic inert matrices. Investigation of the photochemical properties of 3-aminopyrazole revealed its conversion to 5-aminopyrazole under ultraviolet irradiation.

2024-10-18Doctoral thesis

Embargoed access