New direct inhibitors of InhA with antimycobacterial activity based on a tetrahydropyran scaffold Articles uri icon

authors

  • PAJK, STANE
  • ZIVEC, MATEJ
  • SINK, ROMAN
  • SOSIC, IZIDOR
  • NEU, MARGERETE
  • CHUNG, CHUN-WA
  • MARTÍNEZ HOYOS, MARÍA
  • PEREZ HERRAN, ESTHER
  • ÁLVAREZ GÓMEZ, DANIEL
  • ÁLVAREZ RUIZ, EMILIO
  • MENDOZA LOSANA, ALFONSO
  • CASTRO PICHEL, JULIA
  • BARROS, DAVID
  • BALLELL PAGES, LLUÍS
  • YOUNG, ROBERT J.
  • CONVERY, MAIRE A.
  • ENCINAS, LOURDES
  • GOBEC, STANISLAV

publication date

  • February 2016

start page

  • 252

end page

  • 257

volume

  • 112

International Standard Serial Number (ISSN)

  • 0223-5234

Electronic International Standard Serial Number (EISSN)

  • 1768-3254

abstract

  • Tetrahydropyran derivative 1 was discovered in a high-throughput screening campaign to find new inhibitors of mycobacterial InhA. Following initial in-vitro profiling, a structure-activity relationship study was initiated and a focused library of analogs was synthesized and evaluated. This yielded compound 42 with improved antimycobacterial activity and low cytotoxicity. Additionally, the crystal structure of InhA in complex with inhibitor 1 was resolved, to reveal the binding mode and provide hints for further optimization.

keywords

  • inhibitors; inha; tuberculosis; synthesis