Lolamicin

Lolamicin is an experimental antibiotic.^[1] It targets Gram-negative bacteria without significantly affecting typical gut microbes.^[2] Lolamicin was discovered by a team led by Paul Hergenrother at the University of Illinois Urbana-Champaign and was first reported in 2024.^[1]

Lolamicin

Identifiers
CAS Number	2930690-12-1
3D model (JSmol)	Interactive image
ChemSpider	129381266
PubChem CID	168894634
InChI InChI=1S/C24H20N4O/c1-16-9-21(10-17(2)27-16)23-14-26-28-24(23)20-7-4-8-22(12-20)29-15-19-6-3-5-18(11-19)13-25/h3-12,14H,15H2,1-2H3,(H,26,28) Key: CIXIQLLJOWEAKU-UHFFFAOYSA-N
SMILES CC1=CC(=CC(C)=N1)C1=CNN=C1C1=CC=CC(OCC2=CC(=CC=C2)C#N)=C1
Properties
Chemical formula	C24H20N4O
Molar mass	380.451 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

In a mouse model of bacterial infection, lolamicin was found to be especially effective against Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae.^[3]

Lolamicin works by interfering with the lipoprotein transport system of Gram-negative bacteria.^[1]

Synthesis

Lolamicin is synthesized in five steps. Initially, methyl 3-hydroxybenzoate undergoes nucleophilic substitution with 3-(chloromethyl)benzonitrile in the presence of potassium carbonate, forming the corresponding ether. The ester is then hydrolyzed under basic conditions to yield the carboxylic acid. In a two-step process, the carboxylic acid is activated using PyBOP and reacted with N,O-dimethyl hydroxylamine hydrochloride to form the corresponding methoxamide. This intermediate is then subjected to condensation with 2,4,6-collidine under low-temperature conditions using lithium diisopropylamide (LDA), yielding a dimethylpyridine derivative. Finally, treatment with hydrazine monohydrate under reflux promotes cyclization to produce the final pyridine-pyrazole core structure of lolamicin.^[1]