Sulfonamido-2-arylbenzoxazole GroEL/ES Inhibitors as Potent Antibacterials against Methicillin-Resistant Staphylococcus aureus (MRSA)

Abstract

Extending from a study we recently published examining the antitrypanosomal effects of a series of GroEL/ES inhibitors based on a pseudosymmetrical bis-sulfonamido-2-phenylbenzoxazole scaffold, here, we report the antibiotic effects of asymmetric analogs of this scaffold against a panel of bacteria known as the ESKAPE pathogens ( Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). While GroEL/ES inhibitors were largely ineffective against K. pneumoniae, A. baumannii, P. aeruginosa, and E. cloacae (Gram-negative bacteria), many analogs were potent inhibitors of E. faecium and S. aureus proliferation (Gram-positive bacteria, EC values of the most potent analogs were in the 1-2 μM range). Furthermore, even though some compounds inhibit human HSP60/10 biochemical functions in vitro (IC values in the 1-10 μM range), many of these exhibited moderate to low cytotoxicity to human liver and kidney cells (CC values > 20 μM).

3-Amino-5-(indol-3-yl)methylene-4-oxo-2-thioxothiazolidine Derivatives as Antimicrobial Agents: Synthesis, Computational and Biological Evaluation

“…We compared the CC 50 values of compounds 5d , 5k , 5g , 7c with cytotoxicity of the reference drugs obtained in the HEK-293 human embryonic kidney cell line. For antibacterials streptomycin, ampicillin and antifungal bifonazole CC 50 exceeded 100 µM [ 63 , 64 ]; for antifungal ketoconazole CC 50 = 60 µM [ 65 ]. Thus, cytotoxicity of the most active compounds in our study is comparable or lower than cytotoxicity of the reference antimicrobial drugs.…”

Hydroxybiphenylamide GroEL/ES Inhibitors Are Potent Antibacterials against Planktonic and Biofilm Forms of Staphylococcus aureus

“…A nucleophilic aromatic substitution reaction between 2-mercaptobenzothiazole and 3,4-dichloronitrobenzene was employed to give the nitro-intermediate 45 (containing the chloro-group in the R 2 position), which was subsequently reduced to the amine 46 using tin powder in a 10% mixture of HCl in AcOH. 32, 35–38 The intermediate amine 47 , lacking the chloro-group at the R 2 position, was synthesized in one step by a nucleophilic aromatic substitution reaction between 2-chlorobenzothiazole and aminothiophenol. 39 Compounds 17 - 44 were prepared by reacting the respective aryl-acid chlorides (where commercially available) with amines 46 or 47 with pyridine in anhydrous dicloromethane.…”

“…37 The methoxy-bearing analogs ( 29 - 44 ) were then further de-methylated to analogs 1-16 using BBr 3 in anhydrous dichloromethane. 36–38, 40 Detailed synthetic protocols and compound characterizations (e.g. 1 H- NMR, MS, and RP-HPLC) are presented in the Experimental Section and Supporting Information.…”

“…We next evaluated compounds for antibacterial efficacy against the ESKAPE pathogens in liquid media culture as per previously reported procedures. 38 Inhibition EC 50 results for testing of compounds in these bacterial proliferation assays are shown in Table 2. In general, this series of analogs was ineffective against the Gram-negative bacteria ( K. pneumonia , A. baumannii , P. aeruginosa , and E. cloacae ), likely owing to drug efflux and/or impermeability to the lipopolysaccharide (LPS) outer membranes of Gram-negative bacteria.…”

“…These assays were performed as previously reported, with detailed protocols presented in the Supporting Information. 31, 38, 40 Briefly, the HSP60/10-dMDH folding assay was conducted analogously to the GroEL/ES-dMDH folding assay so IC 50 results could be directly compared. The human cell cytotoxicity assays used Alamar Blue reagents to measure the viability of liver and kidney cells that had been incubated with test compounds over a 48 h time period.…”