A combined experimental and in silico characterization to highlight additional structural features and properties of a potentially new drug

Bastos, Ivan Napoleão; Costa, Fanny N.; Silva, Tiago Fiorini da; Barreiro, Eliezer J.; Lima, Lı́dia Moreira; Braz, Delson; Lombardo, Giuseppe M.; Punzo, Francesco; Ferreira, Fábio Furlan; Barroso, R.C.

doi:10.1016/j.molstruc.2017.06.061

Cited by 4 publications

(4 citation statements)

References 48 publications

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“…As previously synthesized and identified by Bastos and coworkers [ 18 ], compound 4a was assigned as the isomer E by X-ray powder diffraction studies. Unlike the mixture of amide conformers ( s -cis and s -trans) identified in solution, the s -cis amide conformation was found by X-ray powder diffraction experiment [ 18 ] ( Figure 2 ).…”

Section: Resultsmentioning

confidence: 91%

“…Taken together, a systematic inferior homologation was applied at the structure of the previous prototype 1 (LASSBio-1514), yielding the design and synthesis of the cyclopentyl-, cyclobutyl- and cyclopropylacylhydrazones, which showed similar in silico physicochemical and drug-like profiles to the parent compound 1 . Compounds revealed a good in vivo anti-inflammatory and antinociceptive profile, allowing the identification of compounds 4e (LASSBio-1757) and 4a (LASSBio-1755, previously synthetized and characterized by Bastos and coworkers [ 18 ]), as new analgesic lead-candidates, active by oral administration in acute and chronic model of pain. Additionally, our data demonstrate the success of the homologation strategy in the design of bioactive compounds.…”

Section: Discussionmentioning

confidence: 99%

“…Compound 4a was obtained as a white powder in 42% yield by condensation of cyclopropanecarbohydrazide ( 10 ) with isonicotinaldehyde, m.p. 193–194 °C, as previously described by Bastos and coworkers (2017) [ 18 ].…”

Section: Methodsmentioning

confidence: 99%

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Design and Synthesis In Silico Drug-like Prediction and Pharmacological Evaluation of Cyclopolymethylenic Homologous of LASSBio-1514

et al. 2021

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Acylhydrazones are still an important framework to the design of new bioactive compounds. As treatment of chronic pain represents a clinical challenge, we decided to modify the structure of LASSBio-1514 (1), previously described as anti-inflammatory and analgesic prototype. Applying the homologation as a strategy for molecular modification, we designed a series of cyclopentyl- (2a–e), cyclobutyl- (3a–e), and cyclopropylacylhydrazones (4a–e) that were synthetized and evaluated in murine models of inflammation and pain. A comparison of their in silico physicochemical and drug-like profile was conducted, as well as their anti-inflammatory and analgesic effect. Compounds 4a (LASSBio-1755) and 4e (LASSBio-1757) displayed excellent in silico drug-like profiles and were identified as new analgesic lead-candidates in acute and chronic model of pain, through oral administration.

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Section: Resultsmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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Design and Synthesis In Silico Drug-like Prediction and Pharmacological Evaluation of Cyclopolymethylenic Homologous of LASSBio-1514

et al. 2021

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“…To determine the crystal structure of both compounds we used the XRPD data, the information previously found in the indexing step and the 3D sketch of LASSBio-1834 ( 3 ) and LASSBio-1835 ( 4 ), created with the program MarvinSketch version 18.10.0-8214, 2018, ChemAxon (). This step was performed using a simulated annealing algorithm implemented into the DASH software program [21], on the basis of previous procedures [22,23,24]. The best result was then considered in the Rietveld refinement of each structure.…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, Experimental and Theoretical Characterization of a New Multitarget 2-Thienyl-N-Acylhydrazone Derivative

et al. 2018

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Pulmonary arterial hypertension (PAH) is a chronic cardiovascular disease that displays inflammatory components, which contributes to the difficulty of adequate treatment with the available therapeutic arsenal. In this context, the N-acylhydrazone derivative LASSBio-1359 was previously described as a multitarget drug candidate able to revert the events associated with the progression of PAH in animal models. However, in spite of having a dual profile as PDE4 inhibitor and adenosine A2A receptor agonist, LASSBio-1359 does not present balanced potencies in the modulation of these two targets, which difficult its therapeutic use. In this paper, we describe the design concept of LASSBio-1835, a novel structural analogue of LASSBio-1359, planned by exploiting ring bioisosterism. Using X-ray powder diffraction, calorimetric techniques, and molecular modeling, we clearly indicate the presence of a preferred synperiplanar conformation at the amide function, which is fixed by an intramolecular 1,5-N∙∙∙S σ-hole intramolecular interaction. Moreover, the evaluation of LASSBio-1835 (4) as a PDE4 inhibitor and as an A2A agonist confirms it presents a more balanced dual profile, being considered a promising prototype for the treatment of PAH.

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Force field and quantum mechanical study of 3-aminopropyltriethoxy silane sorption on hydroxyl free yttria surface

Grassi,

Punzo,

Lombardo

2024

Computational and Theoretical Chemistry

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A combined experimental and in silico characterization to highlight additional structural features and properties of a potentially new drug

Cited by 4 publications

References 48 publications

Design and Synthesis In Silico Drug-like Prediction and Pharmacological Evaluation of Cyclopolymethylenic Homologous of LASSBio-1514

Design and Synthesis In Silico Drug-like Prediction and Pharmacological Evaluation of Cyclopolymethylenic Homologous of LASSBio-1514

Design, Synthesis, Experimental and Theoretical Characterization of a New Multitarget 2-Thienyl-N-Acylhydrazone Derivative

Force field and quantum mechanical study of 3-aminopropyltriethoxy silane sorption on hydroxyl free yttria surface

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