Synthesis of new and potent analogues of anti-tuberculosis agent 5-nitro-furan-2-carboxylic acid 4-(4-benzyl-piperazin-1-yl)-benzylamide with improved bioavailability

Bioorganic & Medicinal Chemistry Letters
Rajendra P TangallapallyRichard E Lee

Abstract

Previously, the lead compound 5-nitro-furan-2-carboxylic acid 4-(4-benzyl-piperazin-1-yl)-benzylamide was identified in our anti-tuberculosis drug discovery program. Although this compound demonstrated excellent in vitro activity, it did not meet the expected in vivo profiles due to structural features that resulted in rapid metabolic cleavage and poor absorption, which therefore limited its bioavailability. In efforts to increase the bioavailability, a new series of analogues was successfully synthesized using three modification schemes: replacement of the benzyl group on the piperazine C-ring with carbamate and urea functional groups; introduction of a nitrogen atom into the aromatic ring-B; and expansion of the ring-B to a bicyclic tetrahydroisoquinoline moiety. These modifications retained strong activity and in some case gained superior anti-tuberculosis activity, increased absorption, and serum half life.

References

Nov 13, 1998·Proceedings of the National Academy of Sciences of the United States of America·C J Murray, J A Salomon
Oct 1, 2004·Journal of Medicinal Chemistry·Rajendra P TangallapallyRichard E Lee
Mar 30, 2006·Antimicrobial Agents and Chemotherapy·Veronica GruppoAnne J Lenaerts

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Citations

Aug 12, 2008·The Journal of Antimicrobial Chemotherapy·Julian G HurdleRichard E Lee
May 1, 2008·The AAPS Journal·Nageshwar R BudhaBernd Meibohm
Mar 24, 2011·Future Medicinal Chemistry·Robert C Goldman
Mar 24, 2011·Future Medicinal Chemistry·Prem M S ChauhanMoni Sharma
Oct 22, 2015·ACS Medicinal Chemistry Letters·Kushalava Reddy YempallaParvinder Pal Singh
Jun 10, 2017·Medicinal Research Reviews·Vajinder KumarRahul Jain
Sep 23, 2008·Magnetic Resonance in Chemistry : MRC·Oluseye K OnajoleHendrik G Kruger
Oct 25, 2007·Biochemical Society Transactions·S T Cole, P M Alzari
Aug 23, 2008·Archiv der Pharmazie·Dalci J BrondaniAna C L Leite
Feb 13, 2007·Bioorganic & Medicinal Chemistry·Yves L Janin

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