32003-14-8Relevant articles and documents
Design, Regiospecific Green Synthesis, Chemical Computational Analysis, and Antimicrobial Evaluation of Novel Phthalazine Heterocycles
Rizk, Sameh A.,Abdelwahab, Salwa S.,El-Badawy, Azza A.
, p. 2347 - 2357 (2019)
Phthalazines have received considerable attention for their wide antimicrobial activity. Regiospecific nucleophilic attack of 4-benzylphthalazin-1-ol by the 1-oxo rather than the aza group on different alkyl halides gave novel phthalazine heterocyclic derivatives. Moreover, a variety of nucleosides bonded to electron-withdrawing groups were synthesized using 4-benzylphthalazine-1-ol. The density functional theory has been used to investigate the electronic structure of the synthesized compounds. All of the synthesized derivatives showed remarkable activity when tested against Gram-positive and Gram-negative bacteria, Aspergillus niger, and Candida albicans. The reactivity of these nucleosides was expected to arise from their bonding with the lone pair of N-atom of the macromolecules of bacteria. These bonding were expected to inhibit the enzyme by forming highly stable complex with lower highest occupied molecular orbital energy. The structures of these synthesized derivatives were established by Fourier transform infrared, 1H-NMR, and 13C-NMR spectroscopic evidence.
Studies towards hypoxia-activated prodrugs of PARP inhibitors
Dickson, Benjamin D.,Wong, Way Wua,Wilson, William R.,Hay, Michael P.
, (2019/05/02)
Poly(ADP-ribose)polymerase (PARP) inhibitors (PARPi) have recently been approved for the treatment of breast and ovarian tumors with defects in homologous recombination repair (HRR). Although it has been demonstrated that PARPi also sensitize HRR competent tumors to cytotoxic chemotherapies or radiotherapy, normal cell toxicity has remained an obstacle to their use in this context. Hypoxia-activated prodrugs (HAPs) provide a means to limit exposure of normal cells to active drug, thus adding a layer of tumor selectivity. We have investigated potential HAPs of model PARPi in which we attach a bioreducible “trigger” to the amide nitrogen, thereby blocking key binding interactions. A representative example showed promise in abrogating PARPi enzymatic activity in a biochemical assay, with a ca. 160-fold higher potency of benzyl phthalazinone 4 than the corresponding model HAP 5, but these N-alkylated compounds did not release the PARPi upon one-electron reduction by radiolysis. Therefore, we extended our investigation to include NU1025, a PARPi that contains a phenol distal to the core binding motif. The resulting 2-nitroimidazolyl ether provided modest abrogation of PARPi activity with a ca. seven-fold decrease in potency, but released the PARPi efficiently upon reduction. This investigation of potential prodrug approaches for PARPi has identified a useful prodrug strategy for future exploration.
Synthesis and vasorelaxant and antiplatelet activities of a new series of (4-Benzylphthalazin-1-ylamino)alcohol derivatives
Munín, Javier,Quezada, Elías,Campos-Toimil, Manuel,Cano, Ernesto,Uriarte, Eugenio,Vi?a, Dolores
, p. 1682 - 1688 (2017/06/27)
A new series of phthalazine derivatives was synthesized by reaction of phthalic anhydride and different substituted phenylacetic acids to yield the benzyliden-3H-isobenzofuran-1-one intermediates 2a–d. Treatment of them with hydrazine afforded 4-benzyl-2H-phthalazin-1-one derivatives 3a–d, which were substituted with the corresponding aminoalkylalcohol to obtain the (4-benzylphthalazin-1-ylamino)alcohol derivatives 4a–h. In general, these phthalazine derivatives relaxed the contractions produced by phenylephrine both in intact or endothelium-denuded aortic rings. In addition, platelet aggregation induced by thrombin was also inhibited by compounds 4c and 4g.
