“Double” Pyrimidine Derivatives: Synthesis and Primary Assessment of Hepatoprotective Properties In Vitro

Russian Journal of Bioorganic Chemistry - “Double” derivatives of the drug Xymedon (1,2-dihydro-4,6-dimethyl-1-N-(hydroxyethyl)pyrimidone-2), hereafter referred to as pyrimidine (I), in...     

Synthesis and primary evaluation of the hepatoprotective properties of novel pyrimidine derivatives

Based on the active ingredient of the drug Ximedon (1,2-dihydro-4,6-dimethyl-1-N-(2-hydroxyethyl)pyrimidone-2, referred below to as pyrimidine (I), novel derivatives containing biogenic acids: succinic, L-ascorbic, para-aminobenzoic, nicotinic, and L-2-amino-4-(methylthio)butanoic (L-methionine) acids have been synthesized. The parameters of acute toxicity (LD₅₀) have been studied. The antitoxic effect of the compounds upon the injury by the hepatotropic poison carbon tetrachloride has been examined as the primary evaluation of their hepatoprotective properties. It has been found that, according to toxicological safety, the compounds synthesized belong to classes III and IV (moderately and little toxic compounds). The conjugates of pyrimidine (I) with ascorbic acid and methionine (LD₅₀ more than 5400 mg/kg) are least toxic. Pyrimidine (I) and its derivatives possess the antitoxic activity upon acute poisoning with carbon tetrachloride; the combined injection of carbon tetrachloride with pyrimidine (I) or its derivatives leads to an increase in the survival of animals and the normalization of the integral functional parameters, weight and body temperature, which decrease upon toxic injury. In addition, pyrimidine (I) and some of its derivatives (conjugates with L-ascorbic, succinic, para-aminobenzoic, and nicotinic acids) decrease the weight coefficients of the liver and kidneys (the organ-to-body-weight ratio) and the activity of transaminases, the markers of hepatic cytolysis, which increase upon toxic injury with carbon tetrachloride. The area of the pathological injury of the liver by steatosis and necrosis decreases by the action of pyrimidine (I) and its novel derivatives (conjugates with L-ascorbic, succinic, and nicotinic acids) two to three times. Advantages of pyrimidine (I) and its novel derivatives over the hepatoprotective drug Thiotriazolin have been revealed.     

Compounds with the dioxopyrimidine cycle inhibit cholinesterases from different groups of animals

We firstly synthesized derivatives of 6-methyluracil, alloxazine, and xanthine, containing omega-tetraalkylammonium (TAA) groups at the N(1) and N(3) atoms in a pyrimidine cycle and assayed their anticholinesterase activities. Compounds with triethylpentylammoniumalkyl groups behaved as typical reversible inhibitors of acetylcholinesterase (AChE) (pI(50) 3.20-6.22) and butyrylcholinesterase (BuChE) (pI(50) 3.05-5.71). Compounds, containing two ethyl residues and a substituted benzyl fragment in the tetraalkylammonium group at N(3) atoms or two similar TAA groups at N(1) and N(3) atoms, possessed very high anticholinesterase activity. Although these compounds displayed the activity of typical irreversible AChE inhibitors (a progressive AChE inactivation; k(i) 7.6x10(8) to 3.5x10(9)M(-1)min(-1)), they were reversible inhibitors of BuChE (pI(50) 3.9-6.9). The efficiency of AChE inhibition by some of these compounds was more than 10(4) times higher than the efficiency of BuChE inhibition. Several synthesized TAA derivates of 6-methyluracil reversibly inhibited electric eel and cobra venom AChEs and horse serum BuChE. However, depending on their structure, the tested compounds possessed the time-progressing inhibition of mammalian erythrocyte AChE, typically of irreversible inhibitors. As shown upon dialysis and gel-filtration, the formed mammalian AChE-inhibitor complex was stable. Thus, a new class of highly active, selective, and irreversible inhibitors of mammalian AChE was described. In contrast to classical phosphorylating or carbamoylating AChE inhibitors, these compounds are devoid of acylating functions. Probably, these inhibitors interact with certain amino acid residues at the entrance to the active-site gorge.