A novel quinoline derivative that inhibits mycobacterial FtsZ

Abstract

High throughput phenotypic screening of large commercially available libraries through two NIH programs has produced thousands of potentially interesting hits for further development as antitubercular agents. Unfortunately, these screens do not supply target information, and further follow up target identification is required to allow optimal rational design and development of highly active and selective clinical candidates. Cheminformatic analysis of the quinoline and quinazoline hits from these HTS screens suggested a hypothesis that certain compounds in these two classes may target the mycobacterial tubulin homolog, FtsZ. In this brief communication, activity of a lead quinoline against the target FtsZ from Mycobacterium tuberculosis (Mtb) is confirmed as well as good in vitro whole cell antibacterial activity against Mtb H37Rv. The identification of a putative target of this highly tractable pharmacophore should help medicinal chemists interested in targeting FtsZ and cell division develop a rational design program to optimize this activity toward a novel drug candidate.

Figure 1

Structures of quinoline compounds 1 and 3 and generalized quinazolines (2) reported by Sirisoma et al. where R₁ = H or Me and R₂ = Cl or Me.

Scheme 1

Synthetic pathway to compound 3. N-methyl-4-propoxyaniline is available via reported methods. Reagents and conditions: a) Conc. HCl, iso-propanol, rt.