5-phenylthiophene derivatives exhibited excellent antifungal activity against Candida albicans, Candida tropicalis and Cryptococcus neoformans. However, optimal compound 7 was inactive against Aspergillus fumigatus and unstable in human liver microsomes in vitro with a half-life of 18.6 min. To discover antifungal agents with a broad spectrum and improve the metabolic properties of the compounds, the scaffold hopping strategy was adopted and a series of 4-phenyl-4,5-dihydrooxazole derivatives were designed and synthesized. It was especially encouraging that compound 22a displayed significant antifungal activities against eight susceptible strains and seven FLC-resistant strains. Furthermore, the potent compound 22a could prevent the formation of fungalbiofilms and displayed satisfactory fungicidal activity. In addition, the metabolic stability of compound 22a was improved significantly, with the half-life of 70.5 min. Compound 22a was almost nontoxic to mammalian A549, MCF-7, HepG2, and 293T cells. Moreover, pharmacokinetic studies in SD rats showed that compound 22a exhibited pharmacokinetic properties with a bioavailability of 15.22% and a half-life of 4.44 h, indicating that compound 22a is worthy of further study.
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http://dx.doi.org/10.1016/j.ejmech.2021.113955 | DOI Listing |
Nat Commun
January 2025
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
Bioorg Med Chem
February 2025
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo P.O. Box 11562, Egypt. Electronic address:
This study investigates a series of newly synthesized compounds, including pyridopyrimidine derivatives (9a-g), tricyclic pyridotriazolopyrimidine analogs (18a-d), and dihydropyrimidinones (22a-i), as apoptotic inducers and inhibitors of phosphatidylinositol-3-kinase α (PI3Kα), with potential anticancer activity. An initial in vitro screening of 60 cancer cell lines identified pyridopyrimidine derivatives 9a-g as promising broad-spectrum anticancer agents, with compound 9e demonstrating the strongest inhibitory activity, particularly against T-47D breast cancer cells. Notably, the antitumor potency of compound 9e surpassed that of Pictilisib, inducing G2-M phase cell cycle arrest and initiating apoptosis through the intrinsic apoptotic pathway.
View Article and Find Full Text PDFMar Drugs
December 2024
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, Pr. 100-letya Vladivostoka 159, 690022 Vladivostok, Russia.
Five new non-holostane di- and trisulfated triterpene pentaosides, conicospermiumosides A-1 (), A-2 (), A-3 (), A-1 (), and A-2 () were isolated from the Far Eastern sea cucumber Levin et Stepanov (Cucumariidae, Dendrochirotida). Twelve known glycosides found earlier in other species were also obtained and identified. The structures of new compounds were established on the basis of extensive analysis of the 1D and 2D NMR spectra, as well as by the HR-ESI-MS data.
View Article and Find Full Text PDFBioorg Chem
December 2024
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan, Shandong 250012, PR China. Electronic address:
Epigenetic-targeted therapy has been applied in the treatment of several types of cancer. Herein, based on the synergistic antitumor effects of co-targeting HDACs and EZH2 in some hematological malignancies, a novel series of tazemetostat-based HDACs/EZH2 dual inhibitors were rationally designed, synthesized, and biologically evaluated. Satisfyingly, compounds 22a and 22b were identified as potent HDACs/EZH2 dual inhibitors with robust antiproliferative activities against one diffuse large-cell B cell lymphomas (DLBCL) cell line harboring EZH2 mutation and multiple acute myeloid leukemia (AML) cell lines.
View Article and Find Full Text PDFChem Asian J
January 2025
College of Science and Engineering, James Cook University,Townsville, Qld, 4811, Australia.
Reaction of lanthanoid tris(3,5-dimethylpyrazolate) compounds, [Ln(Mepz)(thf)] (Ln=La 1 a, Ce, Pr, Dy 1 b, Yb, Lu) with potassium or lithium bistrimethylsilylamide and with or without added 3,5-dimethylpyrazole, or of lanthanoid tris(bistrimethylsilyl)amide complexes with potassium bistrimethylsilylamide and 3,5-dimethylpyrazole have yielded a variety of oxide centred Ln or Ln/(K or Li) multinuclear cages, namely, [LaO(Mepz) K(thf)] (2 a), [LaO(Mepz)Li(MepzH)]⋅0.5Hexane (2 b), [LaO(Mepz)(MepzH)] (2 c) (from heating 1 a in toluene), [CeO(Mepz)K(dme)] (3 a), [CeO(Mepz)Li(thf)]⋅0.5Hexane (3 b) and [Ce(Mepz)Li(thf)] (3 c), which crystallized together, [CeO(Mepz)K(thf)] (3 d), [PrO(Mepz)K(thf)] (4), [DyO(Mepz)K(thf)]⋅THF (5), [YbO(Mepz)K(thf)]⋅THF (6), and [LuO(Mepz)K(thf)]⋅THF (7).
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