Wu, Jie; Mu, Ran; Sun, Mingna; Zhao, Nan; Pan, Miaomiao; Li, Hongshuang; Dong, Yi; Sun, Zhaogang; Bai, Jie; Hu, Minwan; Nathan, Carl F.; Javid, Babak; Liu, Gang published the artcile< Derivatives of Natural Product Agrimophol as Disruptors of Intrabacterial pH Homeostasis in Mycobacterium tuberculosis>, Related Products of 4396-13-8, the main research area is agrimophol derivative antitubercular disruption pH homeostasis Mycobacterium tuberculosis; agrimophol; coumarin; diphenylmethane scaffold; intrabacterial pH homeostasis; pharmacophores.
This article reports the rational medicinal chem. of a natural product, agrimophol (1), as a new disruptor of intrabacterial pH (pHIB) homeostasis in Mycobacterium tuberculosis (Mtb). Through the systematic investigation of the structure-activity relationship of 1, scaffold-hopping of the diphenylmethane scaffold, pharmacophore displacement strategies, and studies of the structure-metabolism relationship, a new derivative 5a was achieved. Compound 5a showed 100-fold increased potency in the ability to reduce pHIB to pH 6.0 and similarly improved mycobactericidal activity compared with 1 against both Mycobacterium bovis-BCG and Mtb. Compound 5a possessed improved metabolic stability in human liver microsomes and hepatocytes, lower cytotoxicity, higher selectivity index, and similar pKa value to natural 1. This study introduces a novel scaffold to an old drug, resulting in improved mycobactericidal activity through decreasing pHIB, and may contribute to the critical search for new agents to overcome drug resistance and persistence in the treatment of tuberculosis.
ACS Infectious Diseases published new progress about Blood proteins Role: BSU (Biological Study, Unclassified), BIOL (Biological Study) (human). 4396-13-8 belongs to class alcohols-buliding-blocks, and the molecular formula is C8H6O5, Related Products of 4396-13-8.
Referemce:
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