Design, Synthesis, and Evaluation of Novel Δ²-Thiazolino 2-Pyridone Derivatives That Potentiate Isoniazid Activity in an Isoniazid-Resistant Mycobacterium tuberculosis Mutant.

Q1 · MEDICINE

Article

Author: Good, James A D ; Harrison, Gregory A ; Flentie, Kelly N ; Mayer Bridwell, Anne E ; Brodin, Priscille ; Tønjum, Tone ; Henry, Frederick L ; Wixe, Torbjörn ; Valenta, Joy ; Sarkar, Souvik ; Chatagnon, Jonathan ; Wang, Erin R ; McKee, Samuel R ; Machelart, Arnaud ; Almqvist, Fredrik ; Vagolu, Siva K ; Stallings, Christina L ; Demirel, Peter

Mycobacterium tuberculosis (Mtb) drug resistance poses an alarming threat to global tuberculosis control. We previously reported that C10, a ring-fused thiazolo-2-pyridone, inhibits Mtb respiration, blocks biofilm formation, and restores the activity of the antibiotic isoniazid (INH) in INH-resistant Mtb isolates. This discovery revealed a new strategy to address INH resistance. Expanding upon this strategy, we identified C10 analogues with improved potency and drug-like properties. By exploring three heterocycle spacers (oxadiazole, 1,2,3-triazole, and isoxazole) on the ring-fused thiazolo-2-pyridone scaffold, we identified two novel isoxazoles, 17h and 17j. 17h and 17j inhibited Mtb respiration and biofilm formation more potently with a broader therapeutic window, were better potentiators of INH-mediated inhibition of an INH-resistant Mtb mutant, and more effectively inhibited intracellular Mtb replication than C10. The (-)17j enantiomer showed further enhanced activity compared to its enantiomer and the 17j racemic mixture. Our potent second-generation C10 analogues offer promise for therapeutic development against drug-resistant Mtb.

01 Feb 2023·European Journal of Medicinal Chemistry

Discovery and biological evaluation of 4,6-pyrimidine analogues with potential anticancer agents as novel colchicine binding site inhibitors

Article

Author: Wang, Yuxi ; Chen, Hao ; Liu, Yinghuan ; Tan, Lun ; Zhang, Jifa ; Wu, Chengyong ; Li, Yuyan

Novel 4,6-pyrimidine analogues were designed and synthesized as colchicine binding site inhibitors (CBSIs) with potent antiproliferative activities. Among them, compound 17j has the most potent activities against 6 human cancer cell lines with IC₅₀ values from 1.1 nM to 4.4 nM, which was 76 times higher than the lead compound 3 in A549 cells. The co-crystal structure of 17j in complex with tubulin confirms the key binding mode at the colchicine binding site. Moreover, 17j inhibited the tubulin polymerization in biochemical assays, depolymerized cellular microtubules, induced the G2/M arrest, inhibited the cell migration, and promoted the initiation of apoptosis. In vivo, 17j effectively inhibits primary tumor growth with tumor growth inhibition rates of 42.51% (5 mg/kg) and 65.42% (10 mg/kg) in A549 xenograft model. Taken together, 17j represents a promising new generation of CBSIs.

26 Jan 2012·Journal of Medicinal ChemistryQ1 · MEDICINE

Fluorocyclines. 1. 7-Fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline: A Potent, Broad Spectrum Antibacterial Agent

Q1 · MEDICINE

Article

Author: Rönn, Magnus ; Sun, Cuixiang ; Plamondon, Louis ; Zhou, Jingye ; Sutcliffe, Joyce A. ; Fyfe, Corey ; Clark, Roger B. ; Grossman, Trudy H. ; O’Brien, William J. ; Xiao, Xiao-Yi ; Hunt, Diana K. ; Zhang, Wu-Yan ; Dunwoody, Nick

This and the accompanying report (DOI: 10.1021/jm201467r ) describe the design, synthesis, and evaluation of a new generation of tetracycline antibacterial agents, 7-fluoro-9-substituted-6-demethyl-6-deoxytetracyclines ("fluorocyclines"), accessible through a recently developed total synthesis approach. These fluorocyclines possess potent antibacterial activities against multidrug resistant (MDR) Gram-positive and Gram-negative pathogens. One of the fluorocyclines, 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline (17j, also known as TP-434, 50th Interscience Conference on Antimicrobial Agents and Chemotherapy Conference , Boston, MA , September 12-15, 2010 , poster F1 - 2157 ), is currently undergoing phase 2 clinical trials in patients with complicated intra-abdominal infections (cIAI).

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Indication	Highest Phase	Country/Location	Organization	Date
Tuberculosis	Preclinical	SE	Umea Universitet	24 Jul 2023

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