Coumarin-Based Inhibitors of Bacillus anthracis and Staphylococcus aureus Replicative DNA Helicase: Chemical Optimization, Biological Evaluation, and Antibacterial Activities

Abstract

The increasing prevalence of drug-resistant bacterial infections demands the development of new antibacterials that are not subject to existing mechanisms of resistance. Previously, we described coumarin-based inhibitors of an underexploited bacterial target, namely, the replicative helicase. Here we report the synthesis and evaluation of optimized coumarin-based inhibitors with 9–18-fold increased potency against S. aureus (Sa) and B. anthracis (Ba) helicases. Compounds 20 and 22 provided the best potency, with IC50 values of 3 and 1 µM, respectively, against the DNA duplex strand-unwinding activities of both B. anthracis and S. aureus helicases without affecting the single strand DNA-stimulated ATPase activity. Selectivity index (SI = CC50/MIC) values against S. aureus and B. anthracis for compound 20 were 33 and 66 and for compound 22 were 20 and 40, respectively. In addition, compounds 20 and 22 demonstrated potent antibacterial activity against multiple ciprofloxacin-resistant MRSA strains with MIC values ranging between 0.5–4.2 µg/mL.

Structure–activity relationship studies of 4-methylcoumarin derivatives as anticancer agents

“…Compounds 4, 12, and 18 were synthesized by the reaction of 2-acetylsuccinate with resorcinol, pyrogallol, and phloroglucinol, respectively, under Pechmann conditions (Chakravarti, 1935;Parmar et al, 1996). In a similar manner, the compounds 5, 13, and 19 were obtained by reaction of diethyl 2-acetylpentanedioate with resorcinol, pyrogallol, and phloroglucinol, respectively (Li et al, 2012;Parmar et al, 1987Parmar et al, , 1996. The hydroxycoumarins 4, 5, 8, 12, 13, and 18 on acetylation with acetic anhydride/pyridine yield the corresponding acetylated derivatives 6, 7, 14, 15, 16, and 20, respectively (Parmar et al, 1987(Parmar et al, , 1988(Parmar et al, , 1996Raj et al, 1996).…”

Bromomethylthioindole Inspired Carbazole Hybrids as Promising Class of Anti-MRSA Agents

“…Of note, the carbazole-based compounds 12 and 19 are about 4−18 times more potent than the recently reported coumarin-based inhibitors against VRE (ATCC 51299). 39 To assess the antibacterial spectrum across other genera, several Gram-negative bacteria, including Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii, were further selected for evaluation. Nevertheless, we observed a significant loss of activities against various Gramnegative bacterial strains as mentioned above.…”

Versatility of 7-Substituted Coumarin Molecules as Antimycobacterial Agents, Neuronal Enzyme Inhibitors and Neuroprotective Agents

“…Apart from an interaction with gyrase, bacterial DNA helicase is another suggested target of selected coumarin derivatives [13][14][15]. Similar to other non-classical coumarin antibiotics, the 7-position on these coumarin derivatives does not contain an amino sugar, but rather a moiety able to undergo hydrophobic interactions with the target site [13][14][15].…”

“…Similar to other non-classical coumarin antibiotics, the 7-position on these coumarin derivatives does not contain an amino sugar, but rather a moiety able to undergo hydrophobic interactions with the target site [13][14][15]. Compound 22 (Figure 1), a 4,8-dimethyl-3-propionic acid coumarin derivative with a 2-(4-chloro[1,1-biphenyl]4-yl)ethyl substitution on the 7-position was the most active helicase inhibitor in this series of 7-substituted biphenyl coumarin derivatives [14]. In this series, the methyl substitution in position 4 of the coumarin structure drastically increased the anti-helicase activity of the compounds.…”