1‐(1H‐Indol‐3‐yl)ethanamine Derivatives as Potent Staphylococcus aureus NorA Efflux Pump Inhibitors

Abstract

The synthesis of 37 1-(1H-indol-3-yl)ethanamine derivatives, including 12 new compounds, was achieved through a series of simple and efficient chemical modifications. These indole derivatives displayed modest or no intrinsic anti-staphylococcal activity. By contrast, several of the compounds restored, in a concentration-dependent manner, the antibacterial activity of ciprofloxacin against Staphylococcus aureus strains that were resistant to fluoroquinolones due to overexpression of the NorA efflux pump. Structure-activity relationships studies revealed that the indolic aldonitrones halogenated at position 5 of the indole core were the most efficient inhibitors of the S. aureus NorA efflux pump. Among the compounds, (Z)-N-benzylidene-2-(tert-butoxycarbonylamino)-1-(5-iodo-1H-indol-3-yl)ethanamine oxide led to a fourfold decrease of the ciprofloxacin minimum inhibitory concentration against the SA-1199B strain when used at a concentration of 0.5 mg L(-1) . To the best of our knowledge, this activity is the highest reported to date for an indolic NorA inhibitor. In addition, a new antibacterial compound, tert-butyl (2-(3-hydroxyureido)-2-(1H-indol-3-yl)ethyl)carbamate, which is not toxic for human cells, was also found.

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

“…183 Among the prepared indole derivatives, compound 17 ( Figure 5) displayed the most promising NorA inhibitory activity with an MPC 4 of 1 µM for ciprofloxacin against SA1199B. 184 In addition, even more potent bis-indole compounds were disclosed in the patent application with compound 5 (Figure 1) as a representative example, which showed an MPC 4 below 0.4 µM for ciprofloxacin against SA1199B. Cytotoxicity assays against three different human cell lines were performed and 5 was considered as noncytotoxic at a concentration of 1 µM.…”

“…Furthermore, another research group was investigating indole nucleus as a promising scaffold for the synthesis of novel antimicrobial agents . Among the prepared indole derivatives, compound 17 (Figure ) displayed the most promising NorA inhibitory activity with an MPC 4 of 1 µM for ciprofloxacin against SA1199B . In addition, even more potent bis ‐indole compounds were disclosed in the patent application with compound 5 (Figure ) as a representative example, which showed an MPC 4 below 0.4 µM for ciprofloxacin against SA1199B.…”

“…Bis ‐indole derivatives constitute another example in which an iodine atom was considered as a potentially labile functionality which could manifest toxicity after its release. Newly synthesized potent analogs thus possessed a chlorine or bromine atom instead (compare 17 ; Figure and 5 ; Figure ) . In addition, the position of the methoxy group on the 2‐phenylquinoline nucleus was recognized as being unimportant in terms of toxicity, but piperidine in the side chain was favored over a N , N ‐diethyl group, thus creating safer compounds ( 4 ; Figure ) .…”

“…Newly synthesized potent analogs thus possessed a chlorine or bromine atom instead (compare 17; Figure 5 and 5; Figure 1). [184][185][186] In addition, the position of the methoxy group on the 2-phenylquinoline nucleus was recognized as being unimportant in terms of toxicity, but piperidine in the side chain was favored over a N,N-diethyl group, thus creating safer compounds (4; Figure 1). 199 Many natural products have been investigated so far in the attempt to obtain less toxic inhibitors, but the main drawback of natural compounds is their structural complexity, often associated with difficulties in establishing a good SAR, thus hindering their further development.…”

Antimicrobial Activities of New Indole Derivatives Containing 1,2,4-Triazole, 1,3,4-Thiadiazole and Carbothioamide

“…10 Tertbutyl (2-(3-hydroxyureido)-2-(1H-indol-3-yl)ethyl) carbamate, which is not toxic to human cells, was also found to be an active indolic NorA inhibitor. 11 Azole-containing compounds such as fluconazole, ketoconazole, and itraconazole are the most widely used antifungal agents in the clinic. 12,13 Despite all the claims, many studies have demonstrated the ineffectiveness of fluconazole against Candida krusei, 14,15 which has been recognized as a potentially multidrug-resistant fungal pathogen.…”