Synthesis and Evaluation of Quinazolines as Inhibitors of the Bacterial Cell Division Protein FtsZ

Abstract

The bacterial cell division protein FtsZ is one of many potential targets for the development of novel antibiotics. Recently, zantrin Z3 was shown to be a cross-species inhibitor of FtsZ; however, its specific interactions with the protein are still unknown. Herein we report the synthesis of analogues that contain a more tractable core structure and an analogue with single-digit micromolar inhibition of FtsZ's GTPase activity, which represents the most potent inhibitor of Escherichia coli FtsZ reported to date. In addition, the zantrin Z3 core has been converted to two potential photo-cross-linking reagents for proteomic studies that could shed light on the molecular interactions between FtsZ and molecules related to zantrin Z3.

Recent advances in the discovery and development of antibacterial agents targeting the cell-division protein FtsZ

“…Based on zantrin Z3(1), a known GTPase inhibitor of Bs- FtsZ (IC 50 24 μM), 77 Nepomuceno et al synthesized several quinazoline analogs as inhibitors of FtsZ and their potency examined. 77 Compound ZZ3(2), the N,N -dimethyl analog of ZZ3(1), was found to be twice as potent as ZZ3(1) (IC 50 12 μM).…”

“…77 Compound ZZ3(2), the N,N -dimethyl analog of ZZ3(1), was found to be twice as potent as ZZ3(1) (IC 50 12 μM). Further SAR study revealed that benzo[g]quinazoline of ZZ3(1) and ZZ3(2) could be replaced by a smaller quinazoline, bearing an ammonium salt side chain, to form the most active compound 10 in this series (IC 50 9 μM).…”

Synthesis and Biological Evaluation of Novel FtsZ‐targeted 3‐arylalkoxy‐2,6‐difluorobenzamides as Potential Antimicrobial Agents

“…The chlorination of 1 with thionyl chloride was followed by reaction with aqueous ammonia to give 3-hydroxybenzamide (2) in a good yield. The alkylation of 2 with alkyl chloride or bromide (sodium iodide was not needed for the reaction with alkyl bromide) in the presence of sodium iodide and potassium carbonate afforded 3-O-alkylbenzamide derivatives (4)(5)(6)(7)(8) in 57-63% yields. Similarly, the alkylation of 2 with phenylalkyl chloride or bromide provided 3-O-arylalkylbenzamide subjected to deprotection of ethoxymethyl group to afford 3-hydroxy-2,6-difluorobenzamide (31) in good yield.…”

Small molecules targeting at the bacterial cell division protein FtsZ as potential antimicrobial agents

“…The SAR study discovered that benzo[g]quinazoline of Zantrin Z3 could be substituted by a smaller quinazoline while the 4-chlorostyryl moiety was critical for inhibitory effect on GTPase activity of FtsZ. Among these analogs, 39 (in Figure 6) having an ammonium salt side chain shows the best potency against GTPase of FtsZ with an IC 50 of 9 μM [113]. …”