Novel second-generation taxoids with systematic modifications at the C2, C10, and C3'N positions were synthesized and their structure-activity relationships studied. A number of these taxoids exhibited exceptionally high potentency against multidrug drug-resistant cell lines, and several taxoids exhibited virtually no difference in potency against the drug-sensitive and drug-resistant cell lines. These exceptionally potent taxoids were termed "third-generation taxoids". 19 (SB-T-1214), 14g (SB-T-121303), and 14i (SB-T-1213031), exhibited excellent activity against paclitaxelresistant ovarian cancer cell lines as well, wherein the drug-resistance is mediated by β-tubulin mutation. These taxoids were found to possess exceptional activity in promoting tubulin assembly, forming numerous very short microtubules similar to those formed by discodermolide. Taxoids 19 and 14g also showed excellent cytotoxicity against 4 pancreatic cancer cell lines, expressing 3-4 multidrug resistant genes. Moreover, taxoid 19 exhibited excellent in vivo efficacy against highly drug-resistant CFPAC-1 pancreatic as well as DLD-1 human colon tumor xenografts in mice.

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...

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