Acute toxicity and hypoglycemic activity of 7-chloro-4-thiosubstituted quinoline
The search for effective and safe pharmacological drugs for the treatment of diabetes is remaining highly valuable issue due to the chronic course of the disease and the need to use antipyretic drugs during the rest of life. Currently, various hypoglycemic agents are presented in the pharmaceutical market and the safety of their application is in priority. The activity of 4-thio-
7-chloroquinoline derivatives as potential hypoglycemic drugs was studied here. The hypoglycemic activity was determined using a One Touch Ultra Plus Flex meter. The approach to glucose determination by this method is based on the reaction of glucose contained in the blood sample with flavin adenine dinucleotide dependent glucose dehydrogenase in the test strip, with the formation of a small electric current. The strength of this current calculates the level of glucose in the blood serum. Sodium 3-(7-chloroquinolin-
4-ylthio)propionate demonstrates a high hypoglycemic activity after its intragastric administration. This compound significantly reduces glucose levels in rats up to 18.1% when compared with baseline and other compounds.
2-(7-Chloroquinoline-4-ylthio)propane and 2-acetamido-3-(7-chloroquinolin-
4-ylthio)propanoic acid had little or no effect on serum glucose. The administration of compound 3 3-(7-chloroquinolin-4-ylthio)propionic acid in experimental animals increases the serum glucose on 19,6% comparing to the basic level. Acute toxicity of 4-thio7-chloro-substituted quinoline was determined with the Prozorovsky express method. The substances were administered once intraperitoneally as a thin aqueous suspension in saline solution (stabilizer - Twin 80) or as a solution of not more than 1 ml. The relationship between the structure of the test compounds and their toxicity is analyzed. It has been established that the mean lethal dose (LD50) of these compounds ranges from 200-800 mg/kg and is classified as low toxic that corresponds to the fourth class of toxicity.
(1) Group, I. D. A. Update of mortality attributable to diabetes for the IDF Diabetes Atlas: Estimates for the year 2013. Diabetes Research and Clinical Practice 2015, 109, 461–465. DOI:10.1016/j.diabres.2015.05.037.
(2) Balabolkin, M.I. Diabetes. 2000, 471. ISBN 5-225-04591-X.
(3) Kalapko, O. N.; Shtrygol`, S. Y.; Paponov, B. V.; and L’Vov, S. V. (2014) Acute toxicity and the hypoglycemic action of N,N΄-(ethane-1,2-dyyil)bis(quinoline-2-carboxamide). Klìnìčna farmacìâ 2014, 18, 41–45. https://doi.org/10.24959/cphj.14.1303.
(4) Kekalainen, P.; Sarlund, H.; Pyorala, K.; and Laakso, M. Hyperinsulinemia cluster predicts the development of type 2 diabetes independently of family history of diabetes. Diabetes Care 1999, 22, 86–92. https://doi.org/10.2337/diacare.22.1.86.
(5) Shchegol, I. M. Diabetes. Nursing 2019, 52–54. doi 10.11603/2411-1597.2019.1.9989.
(6) Barr, R. G.; Nathan, D. M.; Meigs, J. B.; Singer, D. E. Tests of Glycemia for the Diagnosis of Type 2 Diabetes Mellitus. Annals of Internal Medicine 2002, 137, 263. https://doi.org/10.7326/0003-4819-137-4-200208200-00011.
(7) Olokoba, A. B., Obateru, O. A., and Olokoba, L. B. Type 2 Diabetes Mellitus: A Review of Current Trends. Oman Medical Journal 2012, 27, 269–273. doi: 10.5001/omj.2012.68.
(8) Clark, C. M., Fradkin, J. E., Hiss, R. G., Lorenz, R. A., Vinicor, F., and Warren-Boulton, E. Promoting Early Diagnosis and Treatment of Type 2 Diabetes. Jama 2000, 284, 363. https://doi.org/10.1001/jama.284.3.363.
(9) Ong, K. L., Cheung, B. M., Wong, L. Y., Wat, N. M., Tan, K. C., and Lam, K. S. Prevalence, Treatment, and Control of Diagnosed Diabetes in the U.S. National Health and Nutrition Examination Survey 1999–2004. Annals of Epidemiology 2008, 18, 222–229. https://doi.org/10.1016/j.annepidem.2007.10.007.
(10) Lukyanchuk, V. D. Toxicometry of drugs at the preclinical stage: state of the problem, discussion aspects (literature review). Modern problems of toxicologists 1998, 2, 12–14. DOI 10.33273/2663-4570. ISSN 1609-0470.
(11) Zakharov, A. V., Lagunin, A. A., Filimonov, D. A., and Poroikov, V. V. Quantitative Prediction of Antitarget Interaction Profiles for Chemical Compounds. Chemical Research in Toxicology 2012, 25, 2378–2385. https://doi.org/10.1021/tx300247r.
(12) Labenskaya, I. B., Veres, G. M Аcute toxicity of N-acyl S-(2-methylchinolin-4-il) -L-cystine derivatives. Zaporizhzhya National University 2016, 2, 168-175
(13) Brazhko, A., Zavgorodniy, M., Karpun, E., Brazhko, E., Romanenko, Y., and Bogdan, A. Chemometric methods for research of biological activity of quinoline derivatives. ScienceRise 2019, 1, 36–42. DOI: 10.15587/2313-8416.2019.155424.
(14) Brazhko, O. A., Zavgorodniy, M. P. Modern aspects of creating of drugs based QuS-program development. LAP LAMBERT Academic Publishing. 2018.
(15) Brazhko O. A., Zavgorodniy M. P., Lagron A. V., Kornet M. M., Dobrodub I. V., Syntesis and biological activity of derivatives (2-methyl (phenyl)-6-R-quinolin-4-yl-sylfanyl) carboxylic acid. Science Review. 2018, 7, 8-10. http://archive.ws-conference.com/synthesis-and-biological-activity-of-derivatives-2-methyl-phenyl-6-r-quinolin-4-yl-sulphanyl-carboxylic-acids/.
(16) Omelyanchik L. O., Brazhko O. A., Labenskaya I. B., Zavgorodniy M. P., Petrusha Yu. Yu. Biological activity and physicochemical properties N-acid derivatives
S-(2-methylquinolin-4-yl)-L-cysteine. Zaporozhye: Zaporizhzhya National University, 2018, 211.
(17) Zapadnyuk, I. P., Zapadnyuk, V. I., Zachariah, E. A. Laboratory animals. Breeding, keeping, use in experiment 1998, 3, 383.
(18) Prozorovsky, V. B. Tabular express method for determining average effective measures of impact on biological objects. Toxicological Bulletin. 1998 1, 28-32.
(19) Stefanov O. V., editor. Pre-clinical study of drugs (methodical recommendation). Kyiv: Avitsena; 2001 Ukrainian.
(20) European convention for the protection of vertebrate animals used for experimental and other scientific purposes. Strasbourg: Council of Europe, 1986, 123, 51. http://www.arsal.ro/wp-content/uploads/2017/02/ETS-123-1.pdf.
(21) General Ethical Principles of Animal Experiments, Endocrinology. 2003, 8, 142-145.
(22) Sidorov, K. K. On the classification of toxicity of poisons in parenteral routes of administration. Toxicology of new industrial chemicals. 1973, 13, 47-51.