Discovery of sulfonyl hydrazone derivative as a new selective PDE4A and PDE4D inhibitor by lead-optimization approach on the prototype LASSBio-448: In vitro and in vivo preclinical studies

Nunes, Isabelle Karine da Costa; Souza, Everton Tenório de; Martins, Italo Rossi Roseno; Barbosa, Gisele; Moraes, Manoel Oliveira de; Medeiros, Millena de Melo; Silva, Sheyla Welma Duarte; Balliano, Tatiane Luciano; Silva, Bagnólia Araújo da; Silva, Patrícia Machado Rodrigues; Carvalho, Vinícius F.; Martins, Marco A.; Lima, Lı́dia Moreira

doi:10.1016/j.ejmech.2020.112492

Cited by 19 publications

(11 citation statements)

References 41 publications

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“…Each compound was added in excess at phosphate buffer solution pH 5.8 and 7.4 to obtain a supersaturated solution that was kept under stirring for 4 h at 37 °C and then was filtered through a 0.45 µm filter for reading at the corresponding wavelengths. The solubility was determined through the equation of the straight line obtained by the linear regression of the calibration curve of the compounds [ 24 , 25 ].…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues

et al. 2023

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Targeted antitumour therapy has revolutionized the treatment of several types of tumours. Among the validated targets, phosphatidylinositol-3 kinase (PI3K) deserves to be highlighted. Several PI3K inhibitors have been developed for the treatment of cancer, including gedatolisib (4). This inhibitor was elected as a prototype and molecular modifications were planned to design a new series of simplified gedatolisib analogues (5a-f). The analogues were synthesised, and the comparative cytotoxic activity profile was studied in phenotypic models employing solid and nonadherent tumour cell lines. Compound 5f (LASSBio-2252) stood out as the most promising of the series, showing good aqueous solubility (42.38 μM (pH = 7.4); 39.33 μM (pH = 5.8)), good partition coefficient (cLogP = 2.96), cytotoxic activity on human leukemia cell lines (CCRF-CEM, K562 and MOLT-4) and an excellent metabolic stability profile in rat liver microsomes (t1/2 = 462 min; Clapp = 0.058 mL/min/g). The ability of 5f to exert its cytotoxic effect through modulation of the PI3K pathway was demonstrated by flow cytometry analysis in a comparative manner to gedatolisib.

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Section: Methodsmentioning

confidence: 99%

Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues

et al. 2023

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“…While the non-methylated sulfonylhydrazone LASSBio-1624 ( 64 ) was inactive against PDE4, the N -methylated sulfonylhydrazone derivative, LASSBio-1632 ( 65 ), was active, showing anti-asthmatic activity associated with the inhibition of PDE4A (IC 50 = 0.5 μM) and PDE4D (IC 50 = 0.7 μM). The authors also reported that the lead compound was able to block airway hyperreactivity and TNF-α production in lung tissue [ 53 ].…”

Section: The Methylation Effect In Pharmacodynamic Optimizationmentioning

confidence: 99%

“… Exploration of the methylation effect for the discovery of selective PDE4A and PDE4D inhibitors [ 53 ]. …”

Section: Figurementioning

confidence: 99%

The Magic Methyl and Its Tricks in Drug Discovery and Development

2023

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One of the key scientific aspects of small-molecule drug discovery and development is the analysis of the relationship between its chemical structure and biological activity. Understanding the effects that lead to significant changes in biological activity is of paramount importance for the rational design and optimization of bioactive molecules. The “methylation effect”, or the “magic methyl” effect, is a factor that stands out due to the number of examples that demonstrate profound changes in either pharmacodynamic or pharmacokinetic properties. In many cases, this has been carried out rationally, but in others it has been the product of serendipitous observations. This paper summarizes recent examples that provide an overview of the current state of the art and contribute to a better understanding of the methylation effect in bioactive small-molecule drug candidates.

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“…Ken et al found that ferimzone was sensitive to the copper transport gene CoIct1 through genetic and cytological analysis . Ferimzone contains a novel hydrazone skeleton that has been widely used in the areas of drug molecule design, natural product synthesis, and intermediate transformation. − …”

Section: Introductionmentioning

confidence: 99%

Exploration of Fungicidal Activity and Mode of Action of Ferimzone Analogs

Zhang

Liu

et al. 2023

J. Agric. Food Chem.

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Lead discovery and molecular target identification are important for developing novel pesticides. Scaffold hopping, an effective approach of modern medicinal and agrochemical chemistry for a rational design of target molecules, is aiming to design novel molecules with similar structures and similar/better biological performance. Herein, 24 new ferimzone derivatives were designed and synthesized by a scaffold-hopping strategy. In vitro bioassays indicated that compound 5o showed similar potency to ferimzone against Cercospora arachidicola and 2-fold higher potency than ferimzone against Alternaria solani. Compounds 5q, 6a, and 6d displayed fungicidal activity with EC50 values ranging from 1.17 to 3.84 μg/mL against Rhizoctonia solani, and compounds 5q and 6a displayed 1.6–1.8-fold higher activity than ferimzone against Fusarium graminearum. The in vivo bioassays at 200 μg/mL indicated that compound 5q was more potent than ferimzone against Pyricularia oryzae (90% vs 70% efficacy, respectively). Density functional theory (DFT) calculations elucidated the structure–energy relationship. Although the mode of action of ferimzone is still unclear, studies suggested that compound 5q significantly inhibited the growth and reproduction of R. solani, and its energy metabolism pathways (e.g., starch, sucrose, lipids, and glutathione) were seriously downregulated after a 5q treatment.

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Discovery of sulfonyl hydrazone derivative as a new selective PDE4A and PDE4D inhibitor by lead-optimization approach on the prototype LASSBio-448: In vitro and in vivo preclinical studies

Cited by 19 publications

References 41 publications

Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues

Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues

The Magic Methyl and Its Tricks in Drug Discovery and Development

Exploration of Fungicidal Activity and Mode of Action of Ferimzone Analogs

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