Comparative chemical and biological hydrolytic stability of homologous esters and isosteres

Souza, Hygor M R de; Guedes, Jéssica S.; Freitas, Rosana Helena C. N.; Gelves, Luis Gabriel Valdivieso; Fokoue, Harold Hilarion; Sant’Anna, Carlos Maurício R.; Barreiro, Eliezer J.; Lima, Lı́dia Moreira

doi:10.1080/14756366.2022.2027933

Cited by 6 publications

(3 citation statements)

References 40 publications

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“…All substituted compounds demonstrate k obs values lower that the corresponding H-benzoate. Souza et al [21] found that the introduction of bromine in the aromatic ring caused a small increase in the hydrolysis rate of ethylbenzoate in rat plasma, an opposite effect to what is here observed. This effect observed in our study is, probably, mainly due to a decreased affinity of human plasma esterases vs. rat plasma esterases for these substrates.…”

Section: Stability Of the Esters In Plasmacontrasting

confidence: 71%

Benzoic Acid Derivatives as Prodrugs for the Treatment of Tuberculosis

Pais¹,

Magalhães²,

Antoniuk³

et al. 2022

Pharmaceuticals

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One interesting approach to fight tuberculosis is the use of prodrugs that often have shown improved biological activities over drugs with poor absorption or difficulty to cross membranes. Previous studies demonstrate that weak acids such as benzoic acid, present antimycobacterial activity. Moreover, esters of those acids revealed to be a viable alternative since they may diffuse more easily through the cell membranes. Previously we showed that mycobacteria can easily activate benzoic acid esters by conversion to the corresponding acid. Since Zhang postulated that the activity of the acids can be dependent on their pKa, we set up to synthesize a library of benzoates with different electron withdrawing groups (4-chloro, 2,6-dichloro, 3,5-dichloro, 4-nitro, and 3,5 dinitro), to modulate pKa of the liberated acid and different alkoxy substituents (propyl, hexyl, and phenyl) to modulate their lipophilicity, and tested the activity of the esters and the corresponding free acids against mycobacteria. We also studied the activation of the esters by mycobacterial enzymes and the stability of the compounds in buffer and plasma. We concluded that all the benzoates in our study can be activated by mycobacterial enzymes and that the phenyl and hexyl esters presented higher activity than the corresponding free acids, with the nitrobenzoates, and especially the dinitrobenzoates, showing very interesting antitubercular activity that deserve further exploration. Our results did not show a correlation between the activity and the pKa of the acids.

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Section: Stability Of the Esters In Plasmacontrasting

confidence: 71%

Benzoic Acid Derivatives as Prodrugs for the Treatment of Tuberculosis

Pais¹,

Magalhães²,

Antoniuk³

et al. 2022

Pharmaceuticals

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“…To investigate this discrepancy, we conducted several experiments. First, LMH001 is an ester ( Figure 1B ), which is generally susceptible to chemical hydrolysis in water and buffers or sensitive to enzymatic degradation in biological fluids ( de Souza et al, 2022 ). We therefore tested the stability of LMH001 in the FP assay buffer—a standard Hepes based buffer with sodium chloride and tween 20 at physiological pH (HBST).…”

Section: Resultsmentioning

confidence: 99%

Chemical synthesis of a reported p47phox/p22phox inhibitor and characterization of its instability and irreproducible activity

et al. 2023

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The nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) multi-subunit complex is a highly abundant and central source of reactive oxygen species. NOX2 is a key enzyme of the innate immune system involved in antibacterial response, but excessive NOX2 activity is involved in oxidative stress and inflammation in many diseases. Inhibition of NOX2 has great potential as a therapeutic strategy. An intriguing pharmacological approach for inhibiting NOX2 is to target the p47phox subunit and thereby block the protein-protein interaction with p22phox, whereby assembling and activation of NOX2 is prevented. However, the shallow binding pocket of p47phox makes it difficult to develop drug-like p47phox/p22phox inhibitors. Recently, the small molecule LMH001 was reported to inhibit the p47phox/p22phox interaction, reduce endothelial NOX2 activity, and protect mice from angiotensin II-induced vascular oxidative stress. These noteworthy results could have significant impact on the field of NOX2 pharmacology, as specific and efficient inhibitors are scarce. Here, we synthesized and tested LMH001 to have it available as a positive control. We established a robust synthetic route for providing LMH001, but subsequently we experienced that LMH001 is chemically unstable in aqueous buffer. In addition, neither LMH001 nor its breakdown products were able to inhibit the p47phox/p22phox interaction in a non-cellular fluorescence polarization assay. However, LHM001 was a weak inhibitor of NOX2 in a functional cell assay, but with same low potency as one of its breakdown products. These findings question the activity and suggested mechanism of LMH001 and constitute important information for other researchers interested in chemical probes for studying NOX2 biology.

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“…9 In pharmaceutical chemistry and drug development, esters are often used as prodrugs with the purpose of enhancing some properties of parent drugs, such as solubility, oral adsorption, membrane permeability, duration of action, and reducing side effects. [10][11][12][13][14] Some typical examples given approve the structural diversity of esters in commercially available medicines in the world, including aspirin (3), enalapril (4), nitazoxanide (5), and artesunate (6) (Figure 1). Structurally, esters are composed of two components, including carboxylic acids and alcohols/phenols, that are usually present in natural compounds or their derivatives; therefore, natural alcohols/phenols or carboxylic acids are always preferred compounds for ester formation.…”

Section: Introductionmentioning

confidence: 99%

Dihydroartemisinin and zerumbone esters of ataluren and its analogs as anticancer agents and EGFR inhibitors

Tran,

Truong,

Nguyen

et al. 2023

Journal of Chemical Research

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In a five-step procedure, 18 new esters (20a–i and 21a–i) of ataluren and its analogs with dihydroartemisinin and zerumbone were synthesized from methyl 3-cyanobenzoate. The screening for their cytotoxic activity against two cancer cell lines, HepG2 and MCF-7, showed that most esters exhibit activity against the tested cell lines, with IC50 values in the range of 1.61–36.52 µM. Among the tested compounds, ester 21f containing 4-methoxy in structure R did not show cytotoxic activity. The interactions of these new derivatives with the epidermal growth factor receptor protein were also investigated by molecular docking studies. The obtained binding conformation revealed several notable results, demonstrating similarities between molecular modeling theory and experiment. These results contributed to interpreting the in vitro cytotoxicity of esters and proposed the basis for predicting the mechanism of their cytotoxic action.

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Comparative chemical and biological hydrolytic stability of homologous esters and isosteres

Cited by 6 publications

References 40 publications

Benzoic Acid Derivatives as Prodrugs for the Treatment of Tuberculosis

Benzoic Acid Derivatives as Prodrugs for the Treatment of Tuberculosis

Chemical synthesis of a reported p47phox/p22phox inhibitor and characterization of its instability and irreproducible activity

Dihydroartemisinin and zerumbone esters of ataluren and its analogs as anticancer agents and EGFR inhibitors

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