60946-79-4Relevant academic research and scientific papers
Structural insight into the optimization of ethyl 5-hydroxybenzo[g]indol-3-carboxylates and their bioisosteric analogues as 5-LO/m-PGES-1 dual inhibitors able to suppress inflammation
Bruno, Ferdinando,Errico, Suann,Pace, Simona,Nawrozkij, Maxim B.,Mkrtchyan, Arthur S.,Guida, Francesca,Maisto, Rosa,Olga?, Abdurrahman,D'Amico, Michele,Maione, Sabatino,De Rosa, Mario,Banoglu, Erden,Werz, Oliver,Fiorentino, Antonio,Filosa, Rosanna
, p. 946 - 960 (2018)
The release of pro-inflammatory mediators, such as prostaglandines (PGs) and leukotrienes (LTs), arising from the arachidonic acid (AA) cascade, play a crucial role in initiating, maintaining, and regulating inflammatory processes. New dual inhibitors of 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1), that block, at the same time, the formation of PGE2 and LTs, are currently emerged as a highly interesting drug candidates for better pharmacotherapie of inflammation-related disorders. Following our previous studies, we here performed a detailed structure-based design of benzo[g]indol-3-carboxylate derivatives, disclosing several new key factors that affect both enzyme activity. Ethyl 2-(3,4-dichlorobenzyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (4b, RAF-01) and ethyl 2-(3,4-dichlorophenyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (7h, RAF-02) emerged as the most active compounds of the series. Additionally, together with selected structure based analogues, both derivatives displayed significant in vivo anti-inflammatory properties. In conclusion, modeling and experimental studies lead to the discovery of new candidate compounds prone to further developments as multi-target inhibitors of the inflammatory pathway.
Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis
Zhang, Wei,Lun, Shichun,Wang, Shu-Huan,Jiang, Xing-Wu,Yang, Fan,Tang, Jie,Manson, Abigail L.,Earl, Ashlee M.,Gunosewoyo, Hendra,Bishai, William R.,Yu, Li-Fang
, p. 791 - 803 (2018/02/17)
Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound whose X-ray cocrystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally related benzofurans with the aim to improve their potency and bioavailability. Herein, we report our preliminary structure-activity relationship studies around this scaffold, highlighting a natural product-inspired cyclization strategy to form coumestans that are shown to be active in SIT. Whole genome deep sequencing of the coumestan-resistant mutants confirmed a single nucleotide polymorphism in the pks13 gene responsible for the resistance phenotype, demonstrating the druggability of this target for the development of new antitubercular agents.
