Novel Effective Fluorinated Benzothiophene-Indole Hybrid Antibacterials against S. aureus and MRSA Strains

Abstract

Increasing antibacterial drug resistance threatens global health, unfortunately, however, efforts to find novel antibacterial agents have been scaled back by the pharmaceutical industry due to concerns about a poor return on investment. Nevertheless, there is an urgent need to find novel antibacterial compounds to combat antibacterial drug resistance. The synthesis of novel drugs from natural sources is mostly cost-intensive due to those drugs’ complicated structures. Therefore, it is necessary to find novel antibacterials by simple synthesis to become more attractive for industrial production. We succeeded in the discovery of four antibacterial compound (sub)classes accessible in a simple one-pot reaction based on fluorinated benzothiophene-indole hybrids. They have been evaluated against various S. aureus and MRSA strains. Structure- and substituent-dependent activities have been found within the (sub)classes and promising lead compounds have been identified. In addition, bacterial pyruvate kinase was found to be the molecular target of the active compounds. In conclusion, simple one-pot synthesis of benzothiophene-indoles represents a promising strategy for the search of novel antimicrobial compounds.

Antibacterial Activity of Quinoline‐Based Derivatives against Methicillin‐Resistant Staphylococcus aureus and Pseudomonas aeruginosa: Design, Synthesis, DFT and Molecular Dynamic Simulations

“…[36] In perspective on the signifi- cance of indole molecules against Staphylococcus aureus MRSA, a novel class of indole based derivatives was prepared through simple one-pot synthesis of benzothiophene-indoles, which displayed strong activity against a MRSA strain higher than Oxacillin, and Ciprofloxacin. [37] As previously reported, indole was shown to have the ability to prevent MRSA pyruvate kinase (PK), which was proved by the marine alkaloids such as topsentin, spongotine, and hamacanthin, which have antibacterial activity against MRSA in micromolar ranges. [38] Otherwise, the synthesized series of a new asymmetric indole-based bisamidine revealed powerful activity against several MDR Gram-negative pathogens, K. pneumonia and P. aeruginosa, with relative lower MIC values compared to those resistant to the standard drugs, Levofloxacin and Vancomycin, (> 128 μg/ mL).…”

“…In consistence with our results, a significant inhibition effect of sulfonamide indole derivatives against Staphylococcus aureus MRSA was demonstrated by the relatively low MIC values (below 10 μM), which is superior compared to the standard antibacterial drugs sulfathiazole (MIC=501 μM) and norfloxacin (MIC=13 μM) [36] . In perspective on the significance of indole molecules against Staphylococcus aureus MRSA, a novel class of indole based derivatives was prepared through simple one‐pot synthesis of benzothiophene‐indoles, which displayed strong activity against a MRSA strain higher than Oxacillin, and Ciprofloxacin [37] . As previously reported, indole was shown to have the ability to prevent MRSA pyruvate kinase (PK), which was proved by the marine alkaloids such as topsentin, spongotine, and hamacanthin, which have antibacterial activity against MRSA in micromolar ranges [38] .…”

Development of Novel Indole and Coumarin Derivatives as Antibacterial Agents That Target Histidine Kinase in S. aureus

“…Indoles play a vital role in antibacterial drug discovery [50], and verruculogen and tryprostatins A are commonly used antibiotics having indole motifs [51]. Indole diketopiperazine alkaloids (5) [52], benzothiophene-indole hybrids (6) [53] and deoxyribofuranosyl indoles (7) [54] are some of the reported indole derivatives that serve as inhibitors of S. aureus.…”