Zbigniew Malinowski

Application of organolithium and related reagents in synthesis. Part 25: Novel specific synthesis of the 4-arylisochroman-3-acetic acids via conversion of benzoic acids ☆

The transformation of the benzanilides 1 into 4-arylisochroman-3-acetic acids 8 applying the following sequence of reactions is described. At first, the 3-arylphthalides 3 were obtained via metallation [n-BuLi] of benzanilides 1 and subsequent treatment of the generated bis-lithiated anilides 2 with aromatic aldehydes. Next, the 3-arylphthalides 3 were reduced [LiBH4] to phthalanes 5 and then, via reductive metallation [Li/C10H8] and reaction of the generated bis-lithiated species 6 with dimethylformamide, 3-hydroxy-4-arylisochromans 7 were produced. In the final step the isochromans 7 were treated with 1-methoxy-1-trimethylsilyloxyethene in the presence of titanium tetrachloride and furnished 4-arylisochromans-3-acetic acid methyl esters 8 as trans stereoisomers (Ψ-e/e).

Synthesis and Pharmacological Evaluation of N‐(Dimethylamino)ethyl Derivatives of Benzo‐ and Pyridopyridazinones

New N‐(dimethylamino)ethyl derivatives of phthalazinones and pyridopyridazinones 7, 9 were synthesized and assayed as potential analgesic agents in the hot‐plate, tail‐flick, and writhing tests. Pharmacological assay demonstrated that eight (in ten) of the newly synthesized compounds showed antinociceptive activity. Especially, 2‐[2‐(dimethylamino)ethyl]‐4‐phenyl‐2H‐phthalazin‐1‐one 7a showed remarkably higher antinociceptive activity in all tests. This is connected with influence on supraspinal, spinal, and peripheral structures. The decreased sensitivity to the pain stimulus in the hot‐plate was higher than that of metamizole.

A Practical Approach for Preparation of 2‐[(Dialkylamino)‐methyl]‐4‐aryl‐2H‐phthalazin‐1‐ones via Mannich Reaction of 4‐Aryl‐2H‐phthalazin‐1‐ones

Abstract Synthesis of 4‐aryl‐2H‐phthalazin‐1‐ones 5 and their successive conversion, via the Mannich reaction into 2‐[(dialkylamino)‐methyl]‐4‐aryl‐2H‐phthalazin‐1‐ones 6, 7, 8, 9 as a way of regiospecific transformation of the 4‐methoxybenzanilide 1, is described. In addition, the compounds 5b and 7 appeared to be effective complexing ligands for such metal as Cu(II), Ni(II), Fe(II), and Fe(III).

Application of Organolithium and Related Reagents in Synthesis. Part 221. Synthetic Strategies Based on Ortho-Aromatic Metallation. A Concise Regiospecific Conversion of Benzoic Acids into the 4-Pyridyl-2H-Phthalazin-1-Ones

Abstract The synthesis of phthalazin-1-ones 6, 7, 8 via the reaction of 3-hydroxyisoindolin-l-ones 3, 4, 5 with hydrazine hydrate is described. Starting compounds 3, 4, 5 were regiospecifically prepared upon the lithiation (n-BuLi) of the benzanilides 1 and subsequently the reaction of the dilithiated anilides 2 with methyl pyridinecarboxylates.

Synthesis and biological evaluation of some amino- and sulfanyl-3H-quinazolin-4-one derivatives as potential anticancer agents

A series of 6-substituted quinazolinone derivatives were prepared by the reaction of 6-bromoquinazolinones with aryl or alkyl amines and thiols, in the presence of a Pd(OAc)2/Xantphos system, under Buchwald–Hartwig-type reaction conditions. The 6-bromoquinazolinones were obtained in the three-components reaction of 5-bromoisatoic anhydride, triethyl orthoformate and an appropriate amine. Biological screening of the potential cytotoxicity of synthesized compounds on HT29 and HCT116 cell lines, as well as on the lymphocytes, showed that some derivatives of quinazolinone have significant anticancer activities. The detailed synthesis, spectroscopic data, and biological assays were reported.Graphical abstract

Synthesis of N-(2-(Methylamino)ethyl) Derivatives of 2H-Phthalazin-1-ones

Abstract A series of new alkyl, tosyl, acetyl, and tert-butoxycarbonyl derivatives of 2-(2-aminoethyl)-phthalazinones were efficiently synthesized by reaction of lactams with N-Boc-, N-acetyl-, or N,O-ditosyl derivatives of N-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. GRAPHICAL ABSTRACT

New 1(2H)-phthalazinone derivatives as potent nonpeptidic HIV-1 protease inhibitors: molecular docking studies, molecular dynamics simulation, oral bioavailability and ADME prediction

Abstract Molecular docking simulations of compounds 1–7, the newly synthesised 1(2H)-phthalazinone derivatives with N-(dimethylamino)ethyl pendant arm, as potent inhibitors of HIV-1 protease (HIV-1 PR) were performed. The results of calculations show that compounds 1–7 can 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 compound 3 with 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 compound 3 calculated 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 compounds 1–7 indicate 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 compounds 1–7 with HIV-1 PR also suggests a potent feature to combat a drug resistance to HIV-1 PR inhibitors.

Synthesis of Some Novel N-Substituted Phthalazinone and Pyridopyridazinone Derivatives

Abstract Phthalazinone and pyridopyridazinone derivatives 3, 5, and 9 were prepared via reaction ofappropriate lactams 2 and 8 with 2-bromoethylphthalimide, N-tosylaziridine, and N,O-ditosyl derivatives of N-methylethanolamine in a two-step process in the presence of MeONa/MeOH or NaH/dimethylformamide (DMF). Starting compounds 2 and 8 were obtained by reaction of hydrazine hydrate with isoindolinones 1 or azaisoindolinones 6. Selected N-(2-phthalimidoethyl)-phthalazinones were converted into corresponding 2-[2-(methylamino) ethyl]- derivatives in satisfactory yields by treatment with hydrazine. GRAPHICAL ABSTRACT

Synthesis of benzoquinoline derivatives from formyl naphthylamines via Friedländer annulation under metal-free conditions

The synthesis of benzoquinolines and benzoquinolinones via Friedländer-type condensation of aminonaphthalene carbaldehydes with (1) primary or secondary alcohols mediated by urea/KOH or with (2) diketones or β-ketoesters is described. The behavior of naphthalene derivatives in the Friedländer annulation, resulted in the formation of Friedländer or non-Friedländer products, is also presented.Graphical abstract