Synthesis and structure activity relationship studies of novel Staphylococcus aureus Sortase A inhibitors

Abstract

Synthetic methods have been developed for the lead Sortase A inhibitors identified from previous studies. Several derivatives of the lead inhibitor were synthesized to derive preliminary structure activity relationships (SAR). Different regions of the lead inhibitor that are critical for the enzyme activity have been determined by systematic SAR studies. The E stereochemistry of the lead compound was found to be critical for its activity. Replacement of the E double bond with Z double bond or a rigid triple bond reduced the enzyme inhibitory activity in most cases. Reduction of the double bond to a C-C single bond resulted in complete loss of activity. Amide carbonyl and NH groups were also found to be crucial for the activity of this class of inhibitors, as well. Morpholine ring oxygen atom was also found to be important factor for the activity of the lead inhibitor. Preliminary SAR studies led to the identification of compounds with improved enzyme inhibition. The most active compound was found to have an IC50 value of 58εM against the enzyme.

Sortase A: An ideal target for anti-virulence drug development

“…1, Compound 8) inhibited SrtA with an IC 50 of 25 mM and had no effect on bacterial viability [Minimum Inhibitory Concentration (MIC) against S. aureus >200 mg/ml] [48]. Lastly, another group of small SrtA inhibitors that were recently described are the morpholinobenzoate derivatives [49]. The most active compound of the series (Fig.…”

Design of Ca2+‐independent Staphylococcus aureus sortase A mutants

“…Sortase A (SrtA) from Staphylococcus aureus (SaSrtA) is a cysteine transpeptidase that is increasingly being considered as a target for the development of antimicrobial drugs (Chenna et al, 2010; Maresso et al, 2007; Scott et al, 2002). This enzyme covalently attaches surface‐exposed virulence factors to the pentaglycine motif of branched Lipid II, a peptidoglycan precursor (Ton‐That et al, 2004).…”

Designing of potential inhibitors against Staphylococcus aureus sortase A: Combined analogue and structure based approach with in vitro validation

“…A dataset of 149 compounds collected from the literature [15,16,23,24]. Every compound in the data set underwent the same cell growth suppression analysis, which makes the results uniform.…”

“…Till date, most of the inhibitors against sortase A were obtained by traditional methods, channeling the need for discovery of much effective small molecule inhibitors [15][16][17][18][19][20][21] by employing sophisticated computational drug discovery methods. Usage of pharmacophore modeling as a tool for the discovery of novel drugs has turned out to be progressively more popular since this method fine-tunes by considering all the aspects, leading to the discovery of novel and potent inhibitor [22].…”