Novel Trisubstituted Benzimidazoles, Targeting Mtb FtsZ, as a New Class of Antitubercular Agents

Abstract

Libraries of novel trisubstituted benzimidazoles were created through rational drug design. A good number of these benzimidazoles exhibited promising MIC values in the range of 0.5-6 μg/mL (2-15 μM) for their antibacterial activity against Mtb H37Rv strain. Moreover, five of the lead compounds also exhibited excellent activity against clinical Mtb strains with different drugresistance profiles. All lead compounds do not show appreciable cytotoxicity (IC 50 >200 μM) against Vero cells, which inhibit Mtb FtsZ assembly in a dose dependent manner. The two lead compounds unexpectedly showed enhancement of the GTPase activity of Mtb FtsZ. The result strongly suggests that the increased GTPase activity destabilizes FtsZ assembly leading to efficient inhibition of FtsZ polymerization and filament formation. The TEM and SEM analyses of Mtb FtsZ and Mtb cells, respectively, treated with a lead compound strongly suggest that lead benzimidazoles have a novel mechanism of action on the inhibition of Mtb FtsZ assembly and Zring formation. KeywordsMycobacterium tuberculosis; FtsZ; FtsZ inhibitor; drug-resistant Mtb; GTPase; TEM; SEM Tuberculosis (TB) is one of the leading infectious diseases and remains a major global health problem. According to WHO, 9.2 million new cases and 1.7 million deaths from TB have been reported.1 With the emergence of HIV, TB has become the most common opportunistic infection afflicting patients living with AIDS. There are 0.7 million HIVpositive people infected with TB, contributing to 0.2 million deaths worldwide.1 The lethal combination of TB and HIV is fuelling the TB epidemic in many parts of the world, especially Africa.1 Poor chemotherapeutics and the inadequate administration of drugs have lead to the development of multi-drug resistant TB (MDR-TB),2 treatment of which requires administration of more expensive, second line antibiotics for up to two years. In addition, even more alarming cases of extensively drug resistant strains of TB (XDR-TB) that are resistant to both first and second line drugs have been reported.3 Recent findings by WHO * To whom correspondences should be addressed. Phone 631-632-1339; fax 631-632-7942; iojima@notes.cc.sunysb.edu. Supporting Information Available:Synthetic procedures and the characterization data for new benzimidazole intermediates as well as Mtb FtsZ protein preparation. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public AccessAuthor Manuscript J Med Chem. Author manuscript; available in PMC 2012 January 13. Consequently, there is a pressing need for the development of novel TB drugs that are effective against both drug sensitive and resistant Mtb strains.FtsZ, a tubulin homologue, is a highly conserved and ubiquitous bacterial cell division protein. Similar to the process of microtubule formation by tubulin, FtsZ polymerizes in a GTP-dependent manner, forming a highly dynamic cytokinetic structure, designated as the Z-ring, at the center of the cell. 4 -5 The recruitment of the other cell division pro...

Plumbagin inhibits cytokinesis in Bacillus subtilis by inhibiting FtsZ assembly – a mechanistic study of its antibacterial activity

“…Inhibition of FtsZ assembly has been shown to cause bacterial cell elongation and to inhibit bacterial proliferation [3,9,10]. In addition to its critical role in bacterial cytokinesis, FtsZ is a highly conserved protein in prokaryotes [11], thereby making it a promising antibacterial drug target [12][13][14][15].…”

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

“…Through structural analysis of these compounds, Ojima and co-workers synthesized a number of new small organic molecules with the benzimidazole scaffold ( Figure 7) and evaluated their antimicrobial activity against M. tuberculosis H37Rv. Among these compounds, 44 and 45 ( Figure 7) were found to display MIC values lower that 1 μg mL −1 without any significant toxicity (IC 50 > 200 μM) against Vero cells [118]. Further investigation revealed that these compounds also showed similar potency against the drug-resistant M. tuberculosis strains.…”

Identification of Agents Targeting Ftsz Assembly

“…Several trisubstituted benzimidazoles have previously been found to be effective against M. tuberculosis H37Rv strains [88]. Initial SAR studies indicated that a cyclohexyl group at the C2 position and diethylamino, dimethylamino or pyrrolidine group at the C6 position are crucial for antibacterial activity.…”