Coumarin-based inhibitors of Bacillus anthracis and Staphylococcus aureus replicative DNA helicase: chemical optimization, biological evaluation, and antibacterial activities.

Bing Li, Ramdas Pai, Ming Di, Daniel Aiello, Marjorie H Barnes, Michelle M Butler, Tommy F Tashjian, Norton P Peet, Terry L Bowlin, Donald T Moir

Journal of medicinal chemistry 2012 Dec 27

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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 Staphylococcus aureus (Sa) and Bacillus anthracis (Ba) helicases. Compounds 20 and 22 provided the best potency, with IC(50) 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 = CC(50)/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 and 4.2 μg/mL.

Citation

Bing Li, Ramdas Pai, Ming Di, Daniel Aiello, Marjorie H Barnes, Michelle M Butler, Tommy F Tashjian, Norton P Peet, Terry L Bowlin, Donald T Moir. Coumarin-based inhibitors of Bacillus anthracis and Staphylococcus aureus replicative DNA helicase: chemical optimization, biological evaluation, and antibacterial activities. Journal of medicinal chemistry. 2012 Dec 27;55(24):10896-908