Structure-based design of haloperidol analogues as inhibitors of acetyltransferase Eis from <i>Mycobacterium tuberculosis</i> to overcome kanamycin resistance
Ankita Punetha, Keith Green, Atefeh Garzan, Nishad Thamban Chandrika, Melisa J. Willby, Allan H. Pang, Caixia Hou, Selina Y. L. Holbrook, Kyle Krieger, James E. Posey, Tanya Parish, Oleg V. Tsodikov, Sylvie Garneau‐Tsodikova
Abstract
strain K204 overexpressing Eis. The Eis inhibitors generally did not exhibit cytotoxicity against mammalian cells. All tested compounds were modestly metabolically stable in human liver microsomes, exhibiting 30-60% metabolism over the course of the assay. While direct repurposing of haloperidol as an anti-TB agent is unlikely due to its neurotoxicity, this study reveals potential approaches to modifying this chemical scaffold to minimize toxicity and improve metabolic stability, while preserving potent Eis inhibition.
Topics & Concepts
HaloperidolPharmacologyChemistryMycobacterium tuberculosisAntipsychoticMedicineTuberculosisInternal medicineDopamineSchizophrenia (object-oriented programming)PsychiatryPathologyCancer therapeutics and mechanismsTuberculosis Research and EpidemiologyBiochemical and Molecular Research