Designing new antitubercular isoniazid derivatives with improved reactivity and membrane trafficking abilities

Faria, Catarina; Moreira, Tânia; Lopes, Pedro E. M.; Costa, Henrique Silveira; Krewall, Jessica R.; Barton, Callie M.; Santos, Susana; Goodwin, Douglas C.; Machado, Diana; Viveiros, Miguel; Machuqueiro, Miguel; Martins, Filomena

doi:10.1016/j.biopha.2021.112362

Cited by 23 publications

(9 citation statements)

References 42 publications

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“…The structure of the PMF profiles carries information on the physical state of the membrane and is usually very well-correlated with several other membrane properties. ,, Nevertheless, it is not obvious how to assign deviation in specific parts of the profile with the membrane stability and possible deformation due to the presence of different membrane PAINS. Previously, this has been done by looking at the entry/exit energy barriers (size and position) and at the eventual barrier at the center of the membrane when present .…”

Section: Resultsmentioning

confidence: 99%

Optimization of an in Silico Protocol Using Probe Permeabilities to Identify Membrane Pan-Assay Interference Compounds

Magalhães

Reis

Vila-Viçosa

et al. 2022

J. Chem. Inf. Model.

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Membrane pan-assay interference compounds (PAINS) are a class of molecules that interact nonspecifically with lipid bilayers and alter their physicochemical properties. An early identification of these compounds avoids chasing false leads and the needless waste of time and resources in drug discovery campaigns. In this work, we optimized an in silico protocol on the basis of umbrella sampling (US)/molecular dynamics (MD) simulations to discriminate between compounds with different membrane PAINS behavior. We showed that the method is quite sensitive to membrane thickness fluctuations, which was mitigated by changing the US reference position to the phosphate atoms of the closest interacting monolayer. The computational efficiency was improved further by decreasing the number of umbrellas and adjusting their strength and position in our US scheme. The inhomogeneous solubility-diffusion model (ISDM) used to calculate the membrane permeability coefficients confirmed that resveratrol and curcumin have distinct membrane PAINS characteristics and indicated a misclassification of nothofagin in a previous work. Overall, we have presented here a promising in silico protocol that can be adopted as a future reference method to identify membrane PAINS.

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Section: Resultsmentioning

confidence: 99%

Optimization of an in Silico Protocol Using Probe Permeabilities to Identify Membrane Pan-Assay Interference Compounds

Magalhães

Reis

Vila-Viçosa

et al. 2022

J. Chem. Inf. Model.

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“…Finally, it should be noted that these complexes are cations and their calculated P m values are still remarkably high and comparable with most hydrophobic drugs. [81][82][83]…”

Section: Paper Dalton Transactionsmentioning

confidence: 99%

Dual FGFR-targeting and pH-activatable ruthenium–peptide conjugates for targeted therapy of breast cancer

Franco Machado,

Sá,

Pires

et al. 2024

Dalton Trans.

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“…Since then, many isoniazid derivatives have been synthesized, e.g. hydrazones (Fraza ˜o de Faria et al, 2021;Al-Khattaf et al, 2021), carboamides (Martins Gouve ˆa et al, 2022; Gavadia et al, 2023) and naphthoquinones (Reis et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Synthesis, structure, ADME and biological activity of three 2,6-disubstituted thiosemicarbazone derivatives

et al. 2023

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Three new 2,6-disubstituted thiosemicarbazone derivatives of pyridine, namely, 2-{amino[6-(pyrrolidin-1-yl)pyridin-2-yl]methylidene}-N,N-dimethylhydrazine-1-carbothioamide, C13H20N6S, 2-{amino[6-(piperidin-1-yl)pyridin-2-yl]methylidene}-N,N-dimethylhydrazine-1-carbothioamide, C14H22N6S, and 2-[amino(6-phenoxypyridin-2-yl)methylidene]-N,N-dimethylhydrazine-1-carbothioamide monohydrate, C15H17N5OS·H2O, have been synthesized and characterized by NMR spectroscopy and low-temperature single-crystal X-ray diffraction. In addition, their antibacterial and anti-yeast activities have been determined. The ability of the tested compounds to inhibit bacterial growth was comparable to vancomycin as a reference drug. Compared to isoniazid (MIC 0.125 and 8 µg ml−1), the compounds showed the ability to inhibit the growth of Mycobacterium tuberculosis to a moderate degree for the standard strain and at the same level or higher (MIC 4–8 µg ml−1) for the resistant strain. All three compounds adopt the zwitterionic form in the crystal structure regardless of the presence or absence of solvent molecules.

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Designing new antitubercular isoniazid derivatives with improved reactivity and membrane trafficking abilities

Cited by 23 publications

References 42 publications

Optimization of an in Silico Protocol Using Probe Permeabilities to Identify Membrane Pan-Assay Interference Compounds

Optimization of an in Silico Protocol Using Probe Permeabilities to Identify Membrane Pan-Assay Interference Compounds

Dual FGFR-targeting and pH-activatable ruthenium–peptide conjugates for targeted therapy of breast cancer

Synthesis, structure, ADME and biological activity of three 2,6-disubstituted thiosemicarbazone derivatives

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