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 1
H-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-dihydropyrimidin4(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 1
H 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 wereused 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 compound