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Molecular docking simulations of compounds1–7, the newly synthesised 1(2H)-phthalazinone derivatives withN-(dimethylamino)ethyl pendant arm, as potent inhibitors of HIV-1 protease (HIV-1 PR) were performed. The results of calculations show that compounds1–7can form stable complexes with HIV-1 PR and their inhibitory action is mainly based on combination of intermolecular hydrogen bonds and ionic interactions between flexible cationic ammonium moiety of ligands and deprotonated carboxylic residues Asp25 and Asp29 of the target receptor. Molecular dynamics calculation in explicit water environment of the best ranked complex of compound3with HIV-1 PR reveals its high stability with conservation of strong salt bridge interactions during all simulation time. Per-residue decomposition of the binding free energy of HIV-1 PR complex with compound3calculated with the MM-PBSA method shows electrostatic and van der Waals interactions as the main favourable components. Estimated oral bioavailability and calculated absorption, distribution, metabolism and excretion (ADME) descriptors, namely, intestinal absorption, aqueous solubility and blood–brain barrier penetration, for compounds1–7indicate their good pharmacokinetic profile in humans after oral administration. Enthalpically favourable contribution of ligand–receptor salt bridge interactions and hydrogen bonds to binding free energy in calculated complexes of compounds1–7with HIV-1 PR also suggests a potent feature to combat a drug resistance to HIV-1 PR inhibitors. [ABSTRACT FROM AUTHOR]

A series of new alkyl, tosyl, acetyl, andtert-butoxycarbonyl derivatives of 2-(2-aminoethyl)-phthalazinones were efficiently synthesized by reaction of lactams withN-Boc-,N-acetyl-, orN,O-ditosyl derivatives ofN-methylethanolamine in the presence of MeONa or under Mitsunobu reaction conditions. Selected compounds were converted into corresponding 2-[2-(methylamino)ethyl]phthalazinones in good yields. [ABSTRACT FROM PUBLISHER]

Amino- and polyaminophthalazinones were synthesized by the palladium-catalyzed amination (alkyl- and arylamines, polyamines) of 4-bromophthalazinones in good yields. The coordinating properties of selected aminophthalazinones towards Cu(II) ions were investigated and the participation of the nitrogen atoms in the complexation of the metal ion was shown. A biological screening of the potential cytotoxicity of selected synthesized compounds on HT-29 and PC-3 cell lines, as well as on the L-929 cell line, proved that some amino derivatives of phthalazinone show interesting anticancer activities. The detailed synthesis, spectroscopic data, and biological assays are reported., (Copyright © 2021, Malinowski et al.)