Discovery of novel FabF ligands inspired by platensimycin by integrating structure-based design with diversity-oriented synthetic accessibility

Abstract

Martin Fisher, [a,b] Ramkrishna Basak, [a,b] Arnout P. Kalverda, [b] Colin W. G. Fishwick, [a,b] W. Bruce Turnbull [a,b] and Adam Nelson* [a,b] , An approach for designing bioactive small molecules has been developed in which de novo structure-based ligand design (SBLD) was focused on regions of chemical space accessible using a diversity-oriented synthetic approach. The approach was exploited in the design and synthesis of a focused library of platensimycin analogues in which the com plex bridged ring system was replaced with a series of alternative ring systems. The affinity of the resulting compounds for the C163Q mutant of FabF was determined using a WaterLOGSY competition binding assay. Several compounds had significantly improved affinity for the protein relative to a reference ligand. The integration of synthetic accessibility with ligand design enabled focus to be placed on synthetically-accessible regions of chemical space that were relevant to the target protein under investigation.

Antibiotics and Bacterial Resistance in the 21st Century

“…However, other enzymes in this biosynthetic pathway remain unexploited. FabF [β-ketoacyl-acyl carrier protein (ACP) synthase II] in particular has recently received significant attention 403–410 largely due to the 2006 discovery of platensimycin ( 94 ) and its subsequent identification as a FabF inhibitor through an RNA antisense based assay. 411,412–413 This molecule has shown potent activity against broad spectrum of gram positive bacteria by blocking the malonyl-ACP binding site of FabF.…”

Implementation of Diverse Synthetic and Strategic Approaches to Biologically Active Sulfamides

“…The use of solid‐support resins for mono‐ and di‐substituted acyclic sulfamides was also reported (Scheme 12). [50] Employment of a stable and versatile sulfamoylation reagent 10.2 , developed by Winum [45] and applied also by other groups, [51] has been discussed for its reactivity with various amines. Transformation of 10.2 with polystyrene (PS)‐supported benzylamine amine 12.2 to prepare Boc‐substituted sulfamide 12.3 by the reaction of an excess of sulfamoylating agent 10.2 (3 equivalents) and 12.2 was performed to automated library preparation.…”

“…[49] The use of solid-support resins for mono-and di-substituted acyclic sulfamides was also reported (Scheme 12). [50] Employment of a stable and versatile sulfamoylation reagent 10.2, developed by Winum [45] and applied also by other groups, [51] has been discussed for its reactivity with various amines. unwanted challenge, the reaction mixture was cooled to À 78°C before the addition of triethylamine.…”

Review of Platensimycin and Platencin: Inhibitors of β-Ketoacyl-acyl Carrier Protein (ACP) Synthase III (FabH)

“…Fisher et al described an approach to platensimycin analogue design using structure-based ligand design (SBLD), a powerful approach that can facilitate the discovery of bioactive small molecules when high quality structural information is available [40]. They designed and synthesized a series of platensimycin analogous and determined the affinities of these compounds for the C163Q mutant of FabF using a WaterLOGSY [41] competition binding assay.…”