In silico and in vivo screening of triamterene synthetic analogues as promising diuretics

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