Ligand efficiency for antibiotics

Back in October of last year we highlighted a paper in Science that disclosed a new antibiotic targeting the bacterial protein FtsZ. The compound was derived through fragment-based techniques, though at the time no details were provided. A new paper in BMCL now provides some of the early medicinal chemistry, and also introduces an interesting new tool for evaluating antibiotics.

As mentioned in the Science paper, the researchers (led by Prolysis but with a number of contributors from Evotec and Key Organics) started with the fragment-like (MW = 151, 11 heavy atoms) 3-methoxybenzamide. An initial survey of “SAR by catalog” soon moved to the synthesis of analogs that could be assembled in up to four steps from commercially available compounds. This study found that the amide was essential, and only limited substitutions around the aromatic ring were tolerated. Turning to the alkoxy group, the authors took the classic “methyl, ethyl, butyl” approach, but kept going all the way to dodecyl. Intriguingly, a nonyloxy substituent proved to be optimal, better than either 8 or 10 carbon chains. Adding two fluorine atoms to the aromatic ring improved the potency further. Although the paper does not describe the final push to PC190723, the authors do describe the desire to replace the long alkyl chain and its likely attendant problems.



The paper also defines an interesting variation of ligand efficiency:

Antibacterial efficiency = -ln (MIC) / N, where
MIC = minimum inhibitory concentration (mg/ml) and
N = non-hydrogen atoms

Although the metric has a few quirks (for example, low-efficiency compounds can actually have negative numbers), “good” values correspond roughly to good LE values; clinically approved low molecular weight antibiotics have antibacterial efficiencies in the 0.26-0.32 mg/ml/atom range.

So for all you folks working on antibiotics, not only are fragments a viable starting point, you now have a new way to evaluate progress.