Punetha, Ankita; Green, Keith D.; Garzan, Atefeh; Thamban Chandrika, Nishad; Willby, Melisa J.; Pang, Allan H.; Hou, Caixia; Holbrook, Selina Y. L.; Krieger, Kyle; Posey, James E.; Parish, Tanya; Tsodikov, Oleg V.; Garneau-Tsodikova, Sylvie published an article in 2021, the title of the article was Structure-based design of haloperidol analogues as inhibitors of acetyltransferase Eis from Mycobacterium tuberculosis to overcome kanamycin resistance.Application In Synthesis of 4-(4-Chlorophenyl)piperidin-4-ol And the article contains the following content:
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a deadly bacterial disease. Drug-resistant strains of Mtb make eradication of TB a daunting task. Overexpression of the enhanced intracellular survival (Eis) protein by Mtb confers resistance to the second-line antibiotic kanamycin (KAN). Eis is an acetyltransferase that acetylates KAN, inactivating its antimicrobial function. Development of Eis inhibitors as KAN adjuvant therapeutics is an attractive path to forestall and overcome KAN resistance. We discovered that an antipsychotic drug, haloperidol (HPD, 1), was a potent Eis inhibitor with IC50 = 0.39 ± 0.08 μM. We determined the crystal structure of the Eis-haloperidol (1) complex, which guided synthesis of 34 analogs. The structure-activity relationship study showed that in addition to haloperidol (1), eight analogs, some of which were smaller than 1, potently inhibited Eis (IC50 ≤ 1 μM). Crystal structures of Eis in complexes with three potent analogs and droperidol (DPD), an antiemetic and antipsychotic, were determined Three compounds partially restored KAN sensitivity of a KAN-resistant Mtb 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 chem. scaffold to minimize toxicity and improve metabolic stability, while preserving potent Eis inhibition. The experimental process involved the reaction of 4-(4-Chlorophenyl)piperidin-4-ol(cas: 39512-49-7).Application In Synthesis of 4-(4-Chlorophenyl)piperidin-4-ol
The Article related to mycobacterium tuberculosis kanamycin resistance haloperidol analog acetyltransferase eis inhibitor, Placeholder for records without volume info and other aspects.Application In Synthesis of 4-(4-Chlorophenyl)piperidin-4-ol
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Piperidine | C5H11N – PubChem