- Discovery of novel fragments inhibiting O-acetylserine sulphhydrylase by combining scaffold hopping and ligand–based drug design
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Several bacteria rely on the reductive sulphur assimilation pathway, absent in mammals, to synthesise cysteine. Reduction of virulence and decrease in antibiotic resistance have already been associated with mutations on the genes that codify cysteine biosynthetic enzymes. Therefore, inhibition of cysteine biosynthesis has emerged as a promising strategy to find new potential agents for the treatment of bacterial infection. Following our previous efforts to explore OASS inhibition and to expand and diversify our library, a scaffold hopping approach was carried out, with the aim of identifying a novel fragment for further development. This novel chemical tool, endowed with favourable pharmacological characteristics, was successfully developed, and a preliminary Structure–Activity Relationship investigation was carried out.
- Magalh?es, Joana,Franko, Nina,Annunziato, Giannamaria,Welch, Martin,Dolan, Stephen K.,Bruno, Agostino,Mozzarelli, Andrea,Armao, Stefano,Jirgensons, Aigars,Pieroni, Marco,Costantino, Gabriele,Campanini, Barbara
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p. 1444 - 1452
(2018/09/25)
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- Macrocyclic prolinyl acyl guanidines as inhibitors of β-secretase (BACE)
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The synthesis, evaluation, and structure-activity relationships of a class of acyl guanidines which inhibit the BACE-1 enzyme are presented. The prolinyl acyl guanidine chemotype (7c), unlike compounds of the parent isothiazole chemotype (1), yielded compounds with good agreement between their enzymatic and cellular potency as well as a reduced susceptibility to P-gp efflux. Further improvements in potency and P-gp ratio were realized via a macrocyclization strategy. The in vivo profile in wild-type mice and P-gp effects for the macrocyclic analog 21c is presented.
- Boy, Kenneth M.,Guernon, Jason M.,Wu, Yong-Jin,Zhang, Yunhui,Shi, Joe,Zhai, Weixu,Zhu, Shirong,Gerritz, Samuel W.,Toyn, Jeremy H.,Meredith, Jere E.,Barten, Donna M.,Burton, Catherine R.,Albright, Charles F.,Good, Andrew C.,Grace, James E.,Lentz, Kimberley A.,Olson, Richard E.,Macor, John E.,Thompson, Lorin A.
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p. 5040 - 5047
(2015/11/09)
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