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 ; Chatagnon, Jonathan ; Sarkar, Souvik ; Valenta, Joy ; 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.

26 Apr 2012·Journal of Medicinal ChemistryQ1 · MEDICINE

Design, Synthesis, and Structure–Activity Correlations of Novel Dibenzo[b,d]furan, Dibenzo[b,d]thiophene, and N-Methylcarbazole Clubbed 1,2,3-Triazoles as Potent Inhibitors of Mycobacterium tuberculosis

Q1 · MEDICINE

Article

Author: Patpi, Santhosh Reddy ; Sriram, Dharmarajan ; Murthy, Ramalinga ; Kantevari, Srinivas ; Kalivendi, Shasi Vardhan ; Sridhar, Balasubramanian ; T, Anjana Devi ; Jain, Nishant ; Pulipati, Lokesh ; Yogeeswari, Perumal

A molecular hybridization approach is an emerging structural modification tool to design new molecules with improved pharmacophoric properties. In this study, 1,2,3-triazole-based Mycobacterium tuberculosis inhibitors and synthetic and natural product-based tricyclic (carbazole, dibenzo[b,d]furan, and dibenzo[b,d]thiophene) antimycobacterial agents were integrated in one molecular platform to prepare various novel clubbed 1,2,3-triazole hybrids using click chemistry. Structure-activity correlations and in vitro activity against M. tuberculosis strain H37Rv of new analogues revealed the order: dibenzo[b,d]thiophene > dibenzo[b,d]furan > 9-methyl-9H-carbazole series. Two of the most potent M. tuberculosis inhibitors 13h and 13q with MIC = 0.78 μg/mL (∼1.9 μM) displayed a low cytotoxicity and high selectivity index (50-255) against four different human cancer cell lines. These results together provided the potential importance of molecular hybridization and the development of triazole clubbed dibenzo[b,d]thiophene-based lead candidates to treat mycobacterial infections.

Journal of Medicinal Chemistry

Design, Synthesis, and Evaluation of Novel δ²-Thiazolino 2-Pyridone Derivatives That Potentiate Isoniazid Activity in an Isoniazid-Resistant Mycobacterium tuberculosis Mutant

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

By exploring three heterocycle spacers (oxadiazole, 1,2,3-triazole, and isoxazole) on the ring-fused thiazolo-2-pyridone scaffold I [R = 3-MeOC₆H₄, 1-naphthyl, 4-pyridyl, etc.;], II [Ar = 3-CF₃C₆H₄, 4-t-BuC₆H₄, 1-naphthyl, 2-naphthyl], III [R = Ph, 3,5-di-F-C₆H₃, 1-naphthyl, etc.;], and IV [Ar = 3-CF₃C₆H₄, 1-naphthyl], identified two novel isoxazoles, III [R = 4-t-BuC₆H₄, 2-naphthyl].Compounds III [R = 4-t-BuC₆H₄, 2-naphthyl]. 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 III [R = 4-t-BuC₆H₄] enantiomer showed further enhanced activity compared to its enantiomer and the III [R = 4-t-BuC₆H₄] racemic mixtureOur potent second-generation C10 III and IV analogs offer promise for therapeutic development against drug-resistant Mtb.

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

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