Synthesis and Evaluation of 2‐Aminothiophene Derivatives as Staphylococcus aureus Efflux Pump Inhibitors

Abstract

2-aminothiophene derivatives (2AT) in which the thiophene ring is fused with a cycloalkyl or a N-acylated piperidine ring by positions 5 and 6 and carrying a 3-carbethoxy group were synthesized and their bacterial growth and enzyme inhibitory effects against efflux proteins of Staphylococcus aureus leading to resistance to fluoroquinolones and erythromycin (ERY) were investigated. Compounds that most effectively decreases the minimum inhibitory concentrations (MICs) of ciprofloxacin (CIP) were assayed for their dose and time effects on the accumulation and efflux of ethidium bromide (EtBr) in the SA-1 strain. None of the compounds displayed antibacterial activity however, three derivatives carrying 2-amino, 2-aminoacetyl and 2-aminotrifluoroacetyl group enhanced the activity of CIP and ERY by 8-and 16-fold, respectively, and were able to restore the sensitivity of resistant strains, acting as typical efflux pump inhibitors (EPIs). The 2-aminoacetyl and 2-aminotrifluoroacetyl derivatives and two other piperidinyl 2-aminotrifluoroacetyl derivatives increased EtBr accumulation in a dose-and timedependent manner, and one of them was also able to inhibit the EtBr efflux. Taken together, these results represent an important advance in the development of new EPIs, and demonstrate that 2AT represent a good scaffold for developing new antibiotic adjuvants.[a] Dr.

Recent contribution of medicinally active 2-aminothiophenes: A privileged scaffold for drug discovery

“…In 2020, da Cruz et al described the synthesis of 2-ATs (56a-f, 58a-c, 57, 59, 61 and 62) as S. aureus efflux pump inhibitors (Scheme 11). 70 By analogy with former works, 71,72 they decided to synthesize analogs to inhibit NorA efflux pumps of S. aureus 1199B strain. The first step was the formation of N-substituted 2-ATs following Gewald conditions.…”

Thiophene‐containing compounds with antimicrobial activity

“…While none of these compounds had any intrinsic activity against the S. aureus strains in the panel, some of them decreased the MIC values of ciprofloxacin and erythromycin on those strains that express NorA efflux pumps ( S. aureus SA‐1) and MrsA efflux pumps ( S. aureus RN‐4220), respectively, which suggests that these compounds are efflux pump inhibitors. [ 92 ] Specifically, the most active antibacterial agent in the collection was 2‐aminothiophene 84 (Figure 10), which reduced the MIC of erythromycin from 256 to 16 μg/ml, while the reduction of MIC of ciprofloxacin by thiophenes with an unmodified amino group was either absent or insignificant.…”

“…A few amides derived from 2‐aminothiophene‐3‐carboxylates (obtained using cyclohexanone, cycloheptanone, 4‐methylcyclohexanone and t ‐butyl 4‐oxopiperidine‐1‐carboxylate as carbonyl reagents in the Gewald reaction) were shown to re‐establish microbial susceptibility and improve the performance of antibiotics, which indicates that these compounds are efflux pump inhibitors. [ 92 ] Compound 141 (R = CH 3 , R 1 = H, R 2 = OC 2 H 5 ) and compound 143 (R = t ‐butoxycarbonyl, octanoyl or 6‐bromohexanoyl) (Figure 15) promoted either a fourfold or an eightfold decrease of MIC of ciprofloxacin in the case of S. aureus expressing NorA efflux pumps ( S. aureus SA‐1), while amide 141 (R = R 1 = CH 3 , R 2 = OC 2 H 5 ) reversed erythromycin resistance in the case of S. aureus expressing MrsA efflux pumps ( S. aureus RN‐4220) by decreasing the antibiotic's MIC fourfold.…”

Strategic Moves of “Superbugs” Against Available Chemical Scaffolds: Signaling, Regulation, and Challenges

“…340 In addition, thiophene derivatives are known to promote the inhibition of the NorA efflux pump, making the antibiotic ciprofloxacin active against the S. aureus SA-119B strain that constitutively overexpressed the NorA efflux pump. 260,341,342 naphthylmethyl)-piperazine). 343,344 However, the toxicity of EPIs to human cells at higher concentrations has proven to be a downside and has remained a controversy in clinical development.…”

“…These small molecules namely chlorobiocin and SLU-258 are likely to be involved in binding to a site between the lipoyl and β-barrel domains of AcrA, which affects the expression of efflux pump . In addition, thiophene derivatives are known to promote the inhibition of the NorA efflux pump, making the antibiotic ciprofloxacin active against the S. aureus SA-119B strain that constitutively overexpressed the NorA efflux pump. ,, Another best characterized EPI for Gram-positive bacteria is NMP (1-(1-naphthylmethyl)-piperazine). , However, the toxicity of EPIs to human cells at higher concentrations has proven to be a downside and has remained a controversy in clinical development . Some other compounds that act as EPIs are globomycin, carbonyl cyanide m -chlorophenylhydrazone, various quinolines, and aryl piperazine derivatives .…”