Structural and physicochemical characterization of sulfonylhydrazone derivatives designed as hypoglycemic agents

Ibiapino, Amanda Laura; Figueiredo, Laysa Pires de; Lima, Lı́dia Moreira; Barreiro, Eliezer J.; Punzo, Francesco; Ferreira, Fábio Furlan

doi:10.1039/c7nj00074j

Cited by 6 publications

(7 citation statements)

References 34 publications

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“…Considering that electrophilicity and steric access to the cyano group are similar between LASSBio-1771 ( 1 ) and LASSBio-1772 ( 2 ), we hypothesized that conformational differences promoted the methyl effect may influence the affinity and intrinsic activity of these prototypes by the oxidative enzymes. This hypothesis agrees with our previous study that revealed conformational differences between LASSBio-1773 ( 3 ) and LASSBio-1774 ( 4 ) …”

Section: Resultssupporting

confidence: 94%

“…In the M4 metabolite of compound 3 , the dihedral angle H-N–S-C is equal to 176.4°, while in the M5 metabolite of compound 4 , the dihedral angle C-N–S-C is equal to 95.8° (Figure S7). These findings agree with our previous study and support the idea that N -methylation in N -sulfonylhydrazones might influence the recognition of these prototypes upon CYP enzymes. Additionally, our data emphasize how a simple molecular modification could modulate the pharmacokinetics properties, highlighting the importance of metabolite profile investigation in drug discovery …”

Section: Resultssupporting

confidence: 93%

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Methyl Effect on the Metabolism, Chemical Stability, and Permeability Profile of Bioactive N-Sulfonylhydrazones

et al. 2022

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Sulfonylhydrazones are privileged structures with multifaceted pharmacological activity. Exploring the hypoglycemic properties of these organic compounds, we previously revealed a new series of Nsulfonylhydrazones (NSH) as antidiabetic drug candidates. Here, we evaluated the microsomal metabolism, chemical stability, and permeability profile of these NSH prototypes, focusing on the pharmacokinetic differences in N-methylated and non-N-methylated analogs. Our results demonstrated that the N-methylated analogs (LASSBio-1772 and LASSBio-1774) were metabolized by CYP, forming three and one metabolites, respectively. These prototypes exhibited chemical stability at pH 2.0 and 7.4 and brain penetration ability. On the other hand, non-Nmethylated analogs (LASSBio-1771 and LASSBio-1773) were hydrolyzed in acid pH and could not cross the artificial blood−brain barrier. The cyano group in LASSBio-1771 was postulated as a possible site of interaction with the heme group, potentially inhibiting CYP enzymes. Moreover, prototypes with the methyl ester group were metabolized by carboxylesterase, and non-N-methylated analogs did not show oxidative metabolism. The prototypes (except LASSBio-1774) showed excellent gastrointestinal absorption. Altogether, our data support the idea that the methyl effect on NSH strongly alters their pharmacokinetic profile, enhances the recognition by CYP enzymes, promotes brain penetration, and plays a protective effect upon acid hydrolysis.

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Section: Resultssupporting

confidence: 94%

Section: Resultssupporting

confidence: 93%

Methyl Effect on the Metabolism, Chemical Stability, and Permeability Profile of Bioactive N-Sulfonylhydrazones

et al. 2022

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“…X-ray powder diffraction data were used to index the diffraction pattern and to determine the crystal structure of compound 5f (LASSBio-2024). Similar detailed procedures have been reported elsewhere 28–31 . Briefly, compound 5f (LASSBio-2024) crystallized as a monohydrate (C 16 H 14 BN 3 O 4 S⋅H 2 O) in a monoclinic crystal system—space group P 2 1 / c (nr.…”

Section: Resultsmentioning

confidence: 80%

Synthesis and pharmacological evaluation of novel isoquinoline N-sulphonylhydrazones designed as ROCK inhibitors

Oliveira

Guerra

Mermelstein

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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In this study, we synthesized a new congener series of N-sulphonylhydrazones designed as candidate ROCK inhibitors using the molecular hybridization of the clinically approved drug fasudil (1) and the IKK-β inhibitor LASSBio-1524 (2). Among the synthesized compounds, the N-methylated derivative 11 (LASSBio-2065) showed the best inhibitory profile for both ROCK isoforms, with IC50 values of 3.1 and 3.8 µM for ROCK1 and ROCK2, respectively. Moreover, these compounds were also active in the scratch assay performed in human breast cancer MDA-MB 231 cells and did not display toxicity in MTT and LDH assays. Molecular modelling studies provided insights into the possible binding modes of these N-sulphonylhydrazones, which present a new molecular architecture capable of being optimized and developed as therapeutically useful ROCK inhibitors.

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“…The crystal structure of the Nit–OH compound was determined using X-ray powder diffraction data and a simulated annealing approach implemented in DASH software; the detailed procedure is described elsewhere. − Nit–OH crystallized in a monoclinic crystal system and space group Pa (nr. 7).…”

Section: Resultsmentioning

confidence: 99%

Mechanisms for the Deactivation of the Electronic Excited States of α-(2-Hydroxyphenyl)-N-phenylnitrone: From Intramolecular Proton and Charge Transfer to Structure Twisting and Aggregation

et al. 2022

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The search for new prominent chemosensors is significantly related to the rationalization of possible multiple pathways of excited-state deactivation. We have prepared and studied compound α-(2-hydroxyphenyl)-N-phenylnitrone (Nit–OH), observing that Nit–OH is stable in acetonitrile solution under UV–vis light. The experimentally observed 540 nm fluorescence for Nit–OH was shown to be related to excitation at 360 nm from the highest occupied molecular orbital to the lowest unoccupied molecular orbital (HOMO–LUMO transition). Potential energy curves (PECs) for the S1 state of Nit–OH did show that there are structures associated with excited-state intramolecular proton transfer (ESIPT), and the existence of an intramolecular H-bonding was confirmed using X-ray powder diffraction (XRD). Twisted intramolecular charge transfer (TICT) took place following ESIPT, and a nonradiative deactivation at the S1/S0 conical intersection occurred; aggregation-induced emission was observed at 540 nm associated with the formation of a stacked dimer. Anti-Kasha emission from the S2 was proposed based on the dependence of the fluorescence excitation wavelength on Nit–OH concentration. From the calculation of the PEC for the S2 state, we obtained radiative transitions at 379 and 432 nm, similar to the obtained experimental values of 383 and 453 nm. We proposed a Jablonski-like diagram that depicts all experimental and theoretical electronic transitions for Nit–OH, summarizing the unique intricate photophysical behavior of this nitrone derivative.

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Structural and physicochemical characterization of sulfonylhydrazone derivatives designed as hypoglycemic agents

Abstract: By solving and refining the structures of two APIs a complete experimental andin silicophysico-chemical characterization was carried out.

Cited by 6 publications

References 34 publications

Methyl Effect on the Metabolism, Chemical Stability, and Permeability Profile of Bioactive N-Sulfonylhydrazones

Methyl Effect on the Metabolism, Chemical Stability, and Permeability Profile of Bioactive N-Sulfonylhydrazones

Synthesis and pharmacological evaluation of novel isoquinoline N-sulphonylhydrazones designed as ROCK inhibitors

Mechanisms for the Deactivation of the Electronic Excited States of α-(2-Hydroxyphenyl)-N-phenylnitrone: From Intramolecular Proton and Charge Transfer to Structure Twisting and Aggregation

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