*120161*

O. Mykoliv¹, Î. Kovalchuk¹, R. Vynnytska¹, L. Zhurakhivska¹, N. Marintsova¹, N.Ruda², N.Chornoivan², G. Stepanuyk², A. Komar³, G. Zagoriy³, M. Ponomarenko⁴, V. Novikov¹

¹Department of Technology of Biologically Active Substances, Pharmacy and Biotechnology, National University “Lviv Polytechnic”, 79013, Ukraine, Lviv-13, Bandera Str. 12, e-mail: vnovikov@polynet.lviv.ua

²Vinnytsia National N.I. Pyrogov Memorial Medical University, 21018, Ukraine, Vinnytsia, Pyrogov Str, 56

³PJSC “Pharmaceutical company” Darnitsa”, 02093, Ukraine, Kyiv, Boryspilska Str., 13

⁴ P.L.Shupik National Medical Academy of Post-Graduate Education, 04112, Ukraine, Kyiv, Dorogozhytska Str., 9

Synthesis of new amino acid derivatives of 1,4-naphthoquinone and research of their biological activity

One of the chapters of up-to-date pharmaceutical and organic chemistry is the chemistry of quinoid compounds, where an important place is occupied by a naphthoquinone and its derivatives. Compounds of these class are interesting due to its physiological, chemical and physico-chemical properties, that predetermine a variety of high biological activity of 1,4-naphthoquinone derivatives.

As it is known, amino acids are widely used in medical practice. It is explained by their ability to participate in a nitrous exchange, in the synthesis of necessary for normal viability of organism proteins, enzymes, hormones, etc. Therefore with the aim of obtaining new potential drugs, undeniable interest is presented by researches in the synthesis of compounds that contain amino acid fragments and quinoid bond system simultaneously.

For identifing of new physiologically active compounds in the series of quinones the aminoacid derivatives of 1,4-naphthoquinone were synthesized and acute toxicity, anti-ischemic and antihypoxic activities were investigated.

With the aim of synthesis of amino acid derivatives of 1,4-naphtoquinone as initial compound 2,3-dichloro-1,4-naphthoquinone (1) was used. It is able to exchange enough movable atoms of chlorine for various nucleophilic reagents. As amino acid components, α- and β- alanine, histidine, arginine, leucine, methionine, tyrosine, aspartic and glutamic acids were used.

Endurance of 2,3-dichloro-1,4-naphthoquinone (9) with the equimolar amount of corresponding amino acid in a hydroalcoholic medium at 60 ^oÑ during 6 hours in presence of KOH or potassium carbonate allowed to get with good yields of corresponding amino acid substituted 1,4-naphthoquinones. For providing better watersolubility to obtained compounds, with the aim of further biological screening, potassium salts were synthesized (2-11).

The structure of obtained compounds was confirmed by the results of element analysis and spectral data. In IR-spectras of amino acid derivatives of 1,4-naphthoquinone characteristic bands of absorption of valency vibrations of quinoid carbonyl groups and –COOH fragment at 1664-1724 cm^-1, in area of ~3400 ñm^-1 - bands of valency vibrations of NH- groups that interflow with extended bands of absorption of hydroxylic groups. In ¹H NMR-spectras the proton signals are corresponded to the integral intensities and offered structure.

The acute toxicity of the synthesized substances was studied on white nonlinear mise, antihypoxic, anti-ischemic, anticonvulsant, actoprotectant properties and influence on cerebral circulation of blood - on nonlinear rats.

Characterizing data of acute toxicity it is possible to mark that derivatives 2,4,5,6 and 9 according to classification of Sydorova K.K. on the dimension of index LD₅₀ can be attributed to the low-toxic substances, as their LD₅₀ is within the limits of 225-400 mg/kg. Compounds 3,7, 8, 10 and 11 can be attributed to the very low toxic substances, as their index of LD₅₀ is more than 500 mg/kg and is within the limits of 540-650 ìã/êã.

Undertaken studies showed that potassium salts of amino acid derivatives of 1,4-naphthoquinone have antihypoxic, anti-ischemic, cerebroprotectant activities and have stimulant action on the blood supply of cerebrum. Some of the compounds of these set(5,6,7,8,10) according to the value of anti-ischemic effect on the models of acute violation of cerebral supply in doses that are 1-10% from LD₅₀, is competitive with cavinton (5mg/kg) and with piracetam (100 mg/kg), and for a level of the antihypoxic action don’t yield to standard preparation of emoxipin (10 mg/kg). For compound 6 expressive stimulant action on cerebral circulation of blood is characteristic, in a magnitude and duration it twice exceeds the effect of cavinton. For the indicated compound anticonvulsant action is inherent, but it is the weaker than the standard cerebroprotectant carbamazepine.

The wide spectrum of pharmacological properties of the synthesized substances caused the research of actoprotectant compounds among them. Most efficiency was shown by compounds 6,7, that in the level of activity prevailed the standard preparation of bemithyl. For compounds-leaders actoprotectant action in the terms of hypo- and hyperthermia was studied and the possible mechanism of their action was studied out. Results of undertaken studies showed that course of medication (14 days) to the organism of rats of compound 7 assists to adaptive alteration of metabolic processes due to strengthening of aerobic reactions, activation of lipolysis (as an additional source of energy) and antioxidant defence that assists to the improvement of energy supply of skeletal muscles and increase of physical endurance.