Synthesis and biological evaluation of indole core-based derivatives with potent antibacterial activity against resistant bacterial pathogens

Abstract

The emergence of drug resistance in bacterial pathogens is a growing clinical problem that poses difficult challenges in patient management. To exacerbate this problem, there is currently a serious lack of antibacterial agents that are designed to target extremely drug-resistant bacterial strains. Here we describe the design, synthesis and antibacterial testing of a series of 40 novel indole core derivatives, which are predicated by molecular modeling to be potential glycosyltransferase inhibitors. Twenty of these derivatives were found to show in vitro inhibition of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. Four of these strains showed additional activity against Gram-negative bacteria, including extended-spectrum beta-lactamase producing Enterobacteriaceae, imipenem-resistant Klebsiella pneumoniae and multidrug-resistant Acinetobacter baumanii, and against Mycobacterium tuberculosis H37Ra. These four compounds are candidates for developing into broad-spectrum anti-infective agents.

Indole/isatin‐containing hybrids as potential antibacterial agents

“…The indole–imidazoline hybrids 30 (MIC: 6.25 to >100 μg/ml) and 31 (MIC: 6.25 to >100 μg/ml) showed considerable activity against S. aureus and MRSA, whereas hybrids 32 (MIC: ≥640 μg/ml) were devoid of activity, suggesting that the hydrazone linker between indole and imidazoline moieties had a great influence on the activity. [ 75,76 ] In particular, hybrids 30a,b (MIC: 3.13–25 μg/ml) possessed a broad‐spectrum activity against S. aureus , S. saprophyticus , S. pyogenes , S. pneumonia , C. urealyticum , MSSA ATCC‐25923, MSSA (clinical isolate), VRE, multidrug‐resistant A. baumanii , MRSA ATCC‐S‐6007, and eight MRSA clinical isolates. [ 75 ] Thus, these two hybrids were promising candidates for the development of broad‐spectrum anti‐infective agents.…”

“…[ 75,76 ] In particular, hybrids 30a,b (MIC: 3.13–25 μg/ml) possessed a broad‐spectrum activity against S. aureus , S. saprophyticus , S. pyogenes , S. pneumonia , C. urealyticum , MSSA ATCC‐25923, MSSA (clinical isolate), VRE, multidrug‐resistant A. baumanii , MRSA ATCC‐S‐6007, and eight MRSA clinical isolates. [ 75 ] Thus, these two hybrids were promising candidates for the development of broad‐spectrum anti‐infective agents.…”

Recent advances in indole dimers and hybrids with antibacterial activity against methicillin‐resistant Staphylococcus aureus

“…The anti‐MRSA SAR of indole–guanidine hybrids 57 (MIC: 3.12 to >100 µg/ml) and 58 (MIC: 3.12 to >100 µg/ml) indicated that the C‐5 position of indole moiety was more favorable for modification than the C‐6 position, and the chloro group at the para position of the phenyl ring was highly preferred. [ 93 ] Among them, hybrids 57a (MIC: 3.12–12.5 µg/ml) and 58a (MIC: 6.25–12.5 µg/ml) possessed a considerable activity against various Gram‐positive pathogens, including MRSA ATCC‐S‐6007, MRSA (clinical isolate), MSSA ATCC‐25923, MSSA (clinical isolate), VRE, S. saprophyticus , S. pyogenes , and S. pneumoniae , and the molecular modeling predicated that these hybrids were potential glycosyltransferase inhibitors.…”

“…The anti-MRSA SAR of indole-guanidine hybrids 57 (MIC: 3.12 to >100 µg/ml) and 58 (MIC: 3.12 to >100 µg/ml) indicated that the C-5 position of indole moiety was more favorable for modification than the C-6 position, and the chloro group at the para position of the phenyl ring was highly preferred. [93] Among them, hybrids 57a (MIC: pneumoniae, and the molecular modeling predicated that these hybrids were potential glycosyltransferase inhibitors.…”

Design, synthesis and molecular modeling study of substituted indoline-2-ones and spiro[indole-heterocycles] with potential activity against Gram-positive bacteria

“…Indole scaffold represents an interesting class of biologically active heterocyclic compounds. The scaffold possesses diverse biological activities including anti-inflammatory (1), anticonvulsant (2), antidepressant (3), antiallergic (4), antitubercular (5), antidiabetic (6), antiviral (7) and antimicrobial activity (8)(9)(10)(11). Oxindole and other related ring systems also exhibit several biological activities (12)(13)(14)(15).…”