Synthesis, solubility, plasma stability, and pharmacological evaluation of novel sulfonylhydrazones designed as anti-diabetic agents.
Neuropathy is a serious complication of diabetes that has a significant socioeconomic impact, since it frequently demands high levels of health care consumption and compromises labor productivity. Recently, LASSBio-1471 (3) was demonstrated to improve oral glucose tolerance, reduce blood glucose levels, and display an anti-neuropathy effect in a murine streptozotocin-induced diabetes model. In the present work, we describe the design, synthesis, solubility, plasma stability, and pharmacological evaluation of novel sulfonylhydrazone derivatives (referred to herein as compounds 4-9), which were designed by molecular modification based on the structure of the prototype LASSBio-1471 (3). Among the compounds tested, better plasma stability was observed with 4, 5, and 9 in comparison to compounds 6, 7, and 8. LASSBio-1773 (7), promoted not only hypoglycemic activity but also the reduction of thermal hyperalgesia and mechanical allodynia in a murine model of streptozotocin-induced diabetic neuropathic pain.
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; Program of Research in Drug Development, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Gisele
G
Zapata-Sudo
Program of Research in Drug Development, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Isabelle Karine
IK
da Costa Nunes
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; Program of Research in Drug Development, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Josenildo Segundo Chaves
JS
Araujo
Program of Research in Drug Development, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Jaqueline Soares
JS
da Silva
Program of Research in Drug Development, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Department of Anesthesiology, Fluminense Federal University, Rio de Janeiro, Brazil.
Margarete Manhães
MM
Trachez
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.
Tiago Fernandes
TF
da Silva
Program of Research in Drug Development, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Filipe P
FP
da Costa
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; Program of Research in Drug Development, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Roberto Takashi
RT
Sudo
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; Program of Research in Drug Development, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Eliezer J
EJ
Barreiro
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; Program of Research in Drug Development, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Lídia Moreira
LM
Lima
diabetes; druglikeness; hypoglycemic activity; metabolite; plasma stability; sulfonylhydrazone
Pharmacol Res. 2014 Sep;87:113-22
25014183
Pain Pract. 2014 Feb;14(2):167-84
23534696
Endocrinol Metab Clin North Am. 2013 Dec;42(4):747-87
24286949
ACS Med Chem Lett. 2012 Nov 20;4(1):142-5
24900577
Molecules. 2015 Feb 12;20(2):3067-88
25685912
Pain Med. 2008 Sep;9(6):660-74
18828198
Curr Diab Rep. 2013 Aug;13(4):500-8
23771401
Front Cell Neurosci. 2014 Aug 20;8:238
25191225
Qual Life Res. 2015 Dec;24(12):3001-14
26068732
Curr Top Med Chem. 2012;12(19):2037-48
23167793
Diabetes Care. 2010 Oct;33(10):2285-93
20876709
Patient. 2015 Aug;8(4):339-48
25354872
BMJ. 2014 May 06;348:g1799
24803311
Curr Top Med Chem. 2012;12(6):548-84
22242855
J Med Chem. 2016 Jan 28;59(2):655-70
26705137
Pain. 2010 May;149(2):338-44
20227832
Eur J Med Chem. 2015 Jul 15;100:24-33
26069927