Search

Critical analysis of published information related to the features of reaction of 1,4-NCCN-, 1,4-NNCN and 1,5-NCCCN-binucleophiles with cyclic anhydrides of dicarboxylic acids has been presented in the review. It has been shown that the reaction of named anhydrides with 1,4-NCCN-binucleophiles leads to the formation of the imidazole fragment that contains carboxyl-containing moiety. It has been shown that benzimidazole derivatives are among the most studied products of reaction between 1,4-NCCN- and cyclic anhydrides of dicarboxylic acids due to the high availability of initial compounds. The approaches to chemical modification of latter compounds have been discussed as well. It has been found out that 1,4-NNCN-binucleophiles used in reactions with cyclic anhydrides of dicarboxylic acids are mostly presented by amidines and amidrazones. The effects of structures of initial compounds and conditions of reactions on the products of reaction have been described. Literature data shows that the reaction of 1,5-NCCCNbinucleophiles such as amides and hydrazides of anthranilic acid, diamino-substituted polycyclic arenes and 2-azaheterylanilines with cyclic anhydrides of dicarboxylic acids commonly results in the formation of pyrimidine derivatives. It has been established that the application of cyclic anhydrides of non-symmetric dicarboxylic acid as reagents may cause the ambiguity of the reaction pathways. However, the formation of single products of interaction between binucleophiles and non-symmetric anhydrides can be achieved by variation of reaction conditions. The biological activity of the discussed reaction products has been considered in detail. It has been shown that the above-mentioned compounds reveal antibacterial, antifungal, anticancer, immunomodulate, and antidiabetic activities. [ABSTRACT FROM AUTHOR]

The modification of lead-compound aimed to the increasing of activity, decrement of toxicity or improvement of selectivity is one of the most important methods used for elaboration of novel medications. Natural compounds, approved or investigational drugs or just compounds with proved biological activity could be the lead-compound. Often the chemical modification of lead compounds is directed at the enhancement of ligand-biological target interactions. Abovementioned approach, namely structural modification of known drug triamterene was used for purposeful search for novel diuretics. The preliminary prognostication of ligand-target interactions and affinity levels allow to reduce quantity of experimental animals, synthesis, and pharmacological studies costs. Conducted studies revealed the series of promising 6,7-disubstituted pteridine-2,4(1H,3H)-diones with diuretic activity that comparable with pharmacological effect of triamterene. Aim – purposeful search for promising diuretics among structural analogues of triamterene that includes preliminary in silico studies, synthesis and in vivo screening of novel compounds for diuretic activity. Methods used: organic synthesis, physicochemical methods of analysis of organic compounds (NMR ¹H-spectroscopy, chromato-mass spectrometry, elemental analysis). Prediction of affinity for a biological target, prediction of toxicity and lipophilicity of the combinatorial library, which was created on the basis of the drug triamterene, was carried out using computer services. Studies of compounds that affect the excretory function of the kidneys of rats were performed according to the generally accepted method of E.B. Berkhin with water load. Research of the probable mechanism was conducted by flexible molecular docking, as an approach of finding molecules with affinity to a specific biological target. Macromolecular data were downloaded from the Protein Data Bank (PDB) namely, the crystal structures of epithelial sodium channel (ENaC) ((PDB ID – 6WTH). The substantiation of potential diuretics design was conducted by in silico methods (prediction of affinity, ligandenzyme interactions and pharmacokinetic characteristics). The structural modification of triamterene molecule was carried out by replacing of amino-group in positions 2, 4 and 7 by others “pharmacophore” fragments. Abovementioned transformation is aimed at the changing of ligand-enzyme interactions in active site, lipophility and toxicity. Synthesis of 6,7- disubstituted pteridine-2,4(1H,3H)-diones was conducted by condensation 5,6-diamino-2-oxo-(thioxo-)-2,3-dihydropyrimidin- 4(1H)-ones with carbonyl-containing compounds or oxocarboxylic acids. The further modification of obtained compounds was performed by alkylation, hydrazinolysis and nucleophilic addition/elimination. The structure of obtained compounds was proven by elemental analysis, chromato-mass and ¹H NMR-spectral analysis. The studies of synthesized compounds effect on excretion function of kidneys allowed to detect series of promising structural analogues of triamterene that exceed it in pharmacological activity by 27.3-99.0%. The “structure-biological activity” relationship was discussed and perspective of the further search of diuretics among abovementioned compounds were shown. The design of new biologically active compounds with diuretic activity was performed using in silico methodologies and realized by structural modification of the well-known diuretic triamterene. Traditional organic synthesis was used for preparation of target compounds, in vivo experiments were used to detect compounds with significant biological activity. Several effective compounds were identified among pteridines, which exceed the reference drug triamterene in terms of daily diuresis. The obtained results substantiate further purposeful search, in-depth research on experimental pathologies and study of the mechanism of action of potential diuretics among this class of compounds. [ABSTRACT FROM AUTHOR]

The synthesis of 6-chloro-(dichloro-, trichloro)methyl-3-R-6,7-dihydro-2H-[1.2.4] triazino[2,3-c]quinazolin-2-ones and their modification under the action of nucleophilic and/or basic reagents are described in this article. It was shown that 6-chloro-(dichloro-, trichloro)methyl-3-R-6,7-dihydro-2H-[1,2,4]triazino[2,3-c]quinazolin-2-ones can be prepared by cyclocondensation of 3-(aminophenyl)-6-R-1,2;4-triazine-5(2W)-ones with chloro-(dichloro-)acetaldehyde or chloral hydrate. The reactivity of the synthesized compounds toward nucleophilic base morpholine and non-nucleophilic base diisopropylethylamine (DIPEA) under different conditions was studied. It was shown that the prepared compounds under the action of morpholine and/or DIPEA can be converted into the products of substitution, elimination or elimination followed by isomerization and substitution. Refluxing of 6-(chloromethyl)-3-R-6,7-dihydro-2 H-[1.2.4] triazino[2,3-c]quinazoline-2-ones with equimolar quantity of morpholine and 10% excess of DIPEA in ethylene glycol monoethyl ether (EGEE) yielded the products on N-alkylation. 6-(Morpholinomethyl)-3-R-2 H-[1,2,4]triazino[2,3-c]quinazoline-2-ones were obtained by heating of 6-dichloromethyl-3-R-6,7-dihydro-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones with five-fold excess of morpholine in EGEE. Reaction of 3-R-6-(trichloromethyl)-6,7-dihydro-2 H-[1,2,4]triazino[2,3-c]quinazolin-2-ones with three-fold excess of DIPEA in EGEE yielded 3-R-2#-[1,2,4]triazino[2,3-c]quinazoline-2-ones. The physicochemical and spectral characteristics of the prepared compounds were determined and discussed. [ABSTRACT FROM AUTHOR]

Aim. To the purposeful search for the DHFR-inhibitors among substituted pteridine-2,4,7-triones and 7-aryl-(hetaryl-)furo[3,2-g]pteridine-2,4(1H,3H)-diones for further biological research. Methods. In vitro methods, molecular docking, SAR-analysis, statistical methods. Results. The DHFR-inhibitory activity of substituted 1-methylpteridine-2,4,7-triones (2, 3, 4) and 7-aryl-(hetaryl-)furo[3,2-g]pteridine-2,4(1H,3H)-diones (5, 6) was studied. It was established that 6-(2-hydroxy-2-aryl-(hetaryl-)ethyl)-1-methylpteridine-2,4,7(1H,3H,8H)-triones (3) and butyl 2-(7-aryl-(hetaryl-)-1-methyl-2,4-dioxo-1,4-dihydrofuro[3,2-g]pteridine-3(2H)-yl)acetates (6) inhibited DHFR by 14.59-52.11 %, and were less active comparing to methotrexate. It was found that the introduction of aryl moiety with electron-accepting group, naphthyl substituent or electron-accepting heterocycle (furan, thiophene and benzofuran) caused an increase in the DHFR-inhibitory activity. Additionally, it was shown, that annulation of the furan cycle to the pteridine system was reasonable in the scope of new DHFR-inhibitors synthesis. Thereby it may be concluded that the calculated values of affinity are not reliable predictors for the DHFR-inhibiting activity of studied compound. However, the molecular docking study may be used for evaluation of the interactions between the studied inhibitor and active center of DHFR. Conclusions. The conducted primary in vitro screening revealed low or moderate DHFR-inhibiting activity of the synthesized compounds. The visualization of molecular docking showed that despite the structural similarity to methotrexate, the obtained compounds form different ligand-enzyme interactions. The calculated values of affinity cannot be used as predictors of DHFR-inhibiting activity because of the absence of correlation between the abovementioned indicators. The obtained compounds may be of interest for further studies aimed at the search for anti-inflammatory, anti-viral, hypoglycemic, hypotensive, anti-ischemic agents due to the expected low-toxicity associated with the slight DHFR-inhibiting activity. [ABSTRACT FROM AUTHOR]