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Drug Design, Development and Therapy Volume 10, 2016 - Issue
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Original Research

Synthesis, solubility, plasma stability, and pharmacological evaluation of novel sulfonylhydrazones designed as anti-diabetic agents

Gisele Zapata-Sudo1 National Institute of Science and Technology on Drugs and Medicines, Federal University of Rio de Janeiro, Laboratory of Evaluation and Synthesis of Bioactive Compounds, Center of Health Sciences, Rio de Janeiro, Brazil;2 Program of Research in Drug Development, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
,
Isabelle Karine da Costa Nunes2 Program of Research in Drug Development, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
,
Josenildo Segundo Chaves Araujo1 National Institute of Science and Technology on Drugs and Medicines, Federal University of Rio de Janeiro, Laboratory of Evaluation and Synthesis of Bioactive Compounds, Center of Health Sciences, Rio de Janeiro, Brazil;2 Program of Research in Drug Development, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
,
Jaqueline Soares da Silva2 Program of Research in Drug Development, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
,
Margarete Manhães Trachez2 Program of Research in Drug Development, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;3 Department of Anesthesiology, Fluminense Federal University, Rio de Janeiro, Brazil
,
Tiago Fernandes da Silva1 National Institute of Science and Technology on Drugs and Medicines, Federal University of Rio de Janeiro, Laboratory of Evaluation and Synthesis of Bioactive Compounds, Center of Health Sciences, Rio de Janeiro, Brazil
,
Filipe P da Costa2 Program of Research in Drug Development, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
,
Roberto Takashi Sudo1 National Institute of Science and Technology on Drugs and Medicines, Federal University of Rio de Janeiro, Laboratory of Evaluation and Synthesis of Bioactive Compounds, Center of Health Sciences, Rio de Janeiro, Brazil;2 Program of Research in Drug Development, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
,
Eliezer J Barreiro1 National Institute of Science and Technology on Drugs and Medicines, Federal University of Rio de Janeiro, Laboratory of Evaluation and Synthesis of Bioactive Compounds, Center of Health Sciences, Rio de Janeiro, Brazil;2 Program of Research in Drug Development, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
&
Lídia Moreira Lima1 National Institute of Science and Technology on Drugs and Medicines, Federal University of Rio de Janeiro, Laboratory of Evaluation and Synthesis of Bioactive Compounds, Center of Health Sciences, Rio de Janeiro, Brazil;2 Program of Research in Drug Development, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilCorrespondence[email protected]
 show all
Pages 2869-2879 | Published online: 09 Sep 2016

Figures & data

Figure 1 Genesis concept of the novel sulfonylhydrazones 4–9 from molecular modifications based on prototype 3.

Figure 1 Genesis concept of the novel sulfonylhydrazones 4–9 from molecular modifications based on prototype 3.

Figure 2 Reagents and conditions.

Notes: a) NH2NH2·H2O, CHCl3, rt, 4 hours, 91%; b) ArCHO, rt, 0.5 hour, 62%–99%; c) i) phthalic anhydride, 130°C, 2 hours, 93%; ii) ICH3, acetone, 50°C, 18 hours, 72%; iii) NH2NH2·H2O, EtOH, 80°C, 59%.
Figure 2 Reagents and conditions.

Table 1 Physicochemical properties and aqueous solubility of compounds 4–9

Figure 3 In vitro chemical stability.

Notes: Compounds 4–9 (20 µM) were evaluated for their chemical stability at pH 7.4 (A) and at pH 2.0 (B). The percentage of compound remaining was calculated through ratio of peak area at each time point to peak area found at 0 minute multiplied by 100. The values are the mean of at least two experiments in triplicate.
Figure 3 In vitro chemical stability.

Table 2 In vitro stability of compounds 4–9 in rat plasma

Figure 4 Representative chromatograms of LASSBio-1773 (7) (20 µM) and its metabolite formed by incubation with rat plasma.

Notes: (A) Incubation in rat plasma at 0 minute; (B) incubation in rat plasma at 1 hour, and appearance of metabolite (M) formed at 4.57 minutes; (C) HPLC/MS ion scan of M [M-H]− at m/z 363.09 (retention time at 4.57); (D) UV chromatogram of M at 4.57 minutes; (E) synthesized M standard (10); (F) UV chromatogram of standard (10) at 4.57 minutes; (G) co-injection of M standard (10) in 1 hour rat plasma experiment; (H) compound and internal standard (IS) in acetonitrile. IS: internal standard (eg, biphenyl-4-carboxylate methyl, C =20 µM). Apparatus: Shimadzu – LC20AD, column: Kromasil 100-5 C18 250 to 4.6 mm. Mobile phase: 50% acetonitrile, 50% water-gradient, 0.1% formic acid, flow: 1 mL/min. Detector: SPD-M20A (Diode Array); wavelength: 254 nm. The mass spectrometer analyses were performed by the mass spectrometer model Esquire 6000 – ESI Ion Trap MSn System Bruker Daltonics (LASSBio®-UFRJ). ‘M’ refers to the metabolite of the compound.
Abbreviations: HPLC/MS, high performance liquid chromatography/mass spectrometry; min, minutes; Intens, Intensity.
Figure 4 Representative chromatograms of LASSBio-1773 (7) (20 µM) and its metabolite formed by incubation with rat plasma.

Figure 5 Representative chromatograms of LASSBio-1771 (8) (20 µM) and its metabolite formed by incubation with rat plasma.

Notes: (A) Incubation in rat plasma at 0 minute; (B) incubation in rat plasma at 1 hour, and appearance of metabolite (M) formed at 4.57 minutes; (C) HPLC/MS ion scan of M [M-H]− at m/z 363.09 (retention time at 4.57); (D) UV chromatogram of M at 4.57 minutes; (E) co-injection of synthesized standard M (10) in 1 hour rat plasma experiment (M); (F) UV chromatogram of standard (10) at 4.57 minutes. IS: internal standard (eg, methyl biphenyl-4-carboxylate, C =20 µM). Apparatus: Shimadzu – LC20AD, column: Kromasil 100-5 C18 250 to 4.6 mm. Mobile phase: 50% acetonitrile, 50% water-gradient, 0.1% formic acid, flow: 1 mL/min. Detector: SPD-M20A (Diode Array); wavelength: 254 nm. The mass spectrometer analyses were performed by the mass spectrometer model Esquire 6000 – ESI Ion Trap MSn System Bruker Daltonics (LASSBio®-UFRJ).
Abbreviations: HPLC/MS, high performance liquid chromatography/mass spectrometry; min, minutes; UV, ultraviolet spectroscopy; Intens, Intensity.
Figure 5 Representative chromatograms of LASSBio-1771 (8) (20 µM) and its metabolite formed by incubation with rat plasma.

Figure 6 Activity of compounds 4–9 in a murine model of diabetes induced by streptozotocin.

Notes: Compounds were evaluated after a single dose (20 mg·kg−1, intraperitoneally). Values are mean ± standard error of the mean; n=7 per group. Student’s t-test with P<0.05 was considered significant. *P<0.05 compared to the time control. Compound 5 was partially insoluble in DMSO.
Abbreviation: DMSO, dimethyl sulfoxide.
Figure 6 Activity of compounds 4–9 in a murine model of diabetes induced by streptozotocin.

Table 3 Evaluation of blood glucose levels (mg/dL) in diabetic rats treated with vehicle (DMSO) and LASSBio-1773 (7), 50 mg·kg−1, ip for 7 days

Figure 7 Effect of administration of compound 7 (LASSBio-1773) on diabetic neuropathy.

Notes: Temporal changes in paw withdrawal latency (A) and paw withdrawal threshold (B) during 7 days of treatment. Values are expressed as mean ± standard error of the mean; n=5 per group. Two-way analysis of variance test was used for comparison among groups. *P<0.05 compared before treatment (BL) and $P<0.05 compared to vehicle (DMSO).
Abbreviations: DMSO, dimethyl sulfoxide; STZ, streptozotocin; s, seconds.
Figure 7 Effect of administration of compound 7 (LASSBio-1773) on diabetic neuropathy.

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