253679-30-0Relevant academic research and scientific papers
Broadening antifungal spectrum and improving metabolic stablity based on a scaffold strategy: Design, synthesis, and evaluation of novel 4-phenyl-4,5-dihydrooxazole derivatives as potent fungistatic and fungicidal reagents
Cheng, Maosheng,Cui, Hengxian,Jiang, Hong,Liu, Lei,Su, Xin,Sun, Yin,Wu, Tianxiao,Yin, Wenbo,Zhang, Yuxin,Zhao, Dongmei,Zhao, Liyu
, (2021/11/11)
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.
Synthesis, characterization, and biological evaluation of new derivatives targeting MbtI as antitubercular agents
Mori, Matteo,Stelitano, Giovanni,Chiarelli, Laurent R.,Cazzaniga, Giulia,Gelain, Arianna,Barlocco, Daniela,Pini, Elena,Meneghetti, Fiorella,Villa, Stefania
, p. 1 - 17 (2021/02/26)
Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of Mycobacterium tuberculosis (Mtb) have developed resistance against most of the established anti-TB drugs, new therapeutic options are urgently needed. An attractive target for the development of new antitubercular agents is the salicylate synthase MbtI, an essential enzyme for the mycobacterial siderophore biochemical machinery, absent in human cells. A set of analogues of I and II, two of the most potent MbtI inhibitors identified to date, was synthesized, characterized, and tested to elucidate the structural requirements for achieving an efficient MbtI inhibition and a potent antitubercular activity with this class of compounds. The structure-activity relationships (SAR) here discussed evidenced the importance of the furan as part of the pharmacophore and led to the preparation of six new compounds (IV-IX), which gave us the opportunity to examine a hitherto unexplored position of the phenyl ring. Among them emerged 5-(3-cyano-5-(trifluoromethyl)phenyl)furan-2-carboxylic acid (IV), endowed with comparable inhibitory properties to the previous leads, but a better antitubercular activity, which is a key issue in MbtI inhibitor research. Therefore, compound IV offers promising prospects for future studies on the development of novel agents against mycobacterial infections.
ERR INVERSE AGONISTS
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Page/Page column 63-64, (2019/03/05)
In one aspect, the present disclosure describes new estrogen receptor-related orphan receptor (EER) inverse agonist compounds. Also described are pharmaceutical formulations, methods of synthesis and uses thereof.
Development and characterization of new inhibitors of the human and mouse hematopoietic prostaglandin D2 synthases
Christ, Angelika N.,Labzin, Larisa,Bourne, Gregory T.,Fukunishi, Hirotada,Weber, Jane E.,Sweet, Matthew J.,Smythe, Mark L.,Flanagan, Jack U.
experimental part, p. 5536 - 5548 (2010/11/17)
The hematopoietic prostaglandin D2 synthase has a proinflammatory effect in a range of diseases, including allergic asthma, where its product prostaglandin D2 (PGD2) has a role in regulating many of the hallmark disease characteristics. Here we describe the development and characterization of a novel series of hematopoietic prostaglandin D2 synthase inhibitors with potency similar to that of known inhibitors. Compounds N-benzhydryl-5-(3-hydroxyphenyl)thiophene-2- carboxamide (compound 8) and N-(1-amino-1-oxo-3-phenylpropan-2-yl)-6-(thiophen- 2-yl)nicotinamide (compound 34) demonstrated low micromolar potency in the inhibition of the purified enzyme, while only 34 reduced Toll-like receptor (TLR) inducible PGD2 production in both mouse primary bone marrow-derived macrophages and the human megakaryocytic cell line MEG-01S. Importantly, 34 demonstrated a greater selectivity for inhibition of PGD 2 synthesis versus other eicosanoids that lie downstream of PGH 2 (PGE2 and markers of prostacyclin (6-keto PGF 1?) and thromboxane (TXB2)) when compared to the known inhibitors HQL-79 (compound 1) and 2-phenyl-5-(1H-pyrazol-3-yl)thiazole (compound 2). Compound 34 therefore represents a selective hematopoietic prostaglandin D2 synthase inhibitor.
