Synthesis and structure-activity relationships for a new class of tetrahydronaphthalene amide inhibitors of Mycobacterium tuberculosis

Sutherland, Hamish S.; Tong, Amy S.T.; Conole, Daniel; Franzblau, Scott G.; Upton, Anna M.; Lotlikar, Manisha U.; Cooper, Christopher B.; Palmer, Brian D.; Blaser, Adrian; Denny, William A.

doi:10.1016/j.ejmech.2021.114059

Cited by 8 publications

(4 citation statements)

References 23 publications

(32 reference statements)

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“…A new class of selective and potent inhibitors of the mycobacterial F 1 ·F o appeared to be tetrahydronaphthalene amides (THNAs). THNAs are effective in preventing the growth of M. tuberculosis in culture and show improved hERG liability, clearance, and half-life compared to bedaquiline [ 136 ].…”

Section: Mycobacterium Tuberculosis F 1 ∙...mentioning

confidence: 99%

F1·Fo ATP Synthase/ATPase: Contemporary View on Unidirectional Catalysis

Zharova

Grivennikova

Borisov

2023

IJMS

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F1·Fo-ATP synthases/ATPases (F1·Fo) are molecular machines that couple either ATP synthesis from ADP and phosphate or ATP hydrolysis to the consumption or production of a transmembrane electrochemical gradient of protons. Currently, in view of the spread of drug-resistant disease-causing strains, there is an increasing interest in F1·Fo as new targets for antimicrobial drugs, in particular, anti-tuberculosis drugs, and inhibitors of these membrane proteins are being considered in this capacity. However, the specific drug search is hampered by the complex mechanism of regulation of F1·Fo in bacteria, in particular, in mycobacteria: the enzyme efficiently synthesizes ATP, but is not capable of ATP hydrolysis. In this review, we consider the current state of the problem of “unidirectional” F1·Fo catalysis found in a wide range of bacterial F1·Fo and enzymes from other organisms, the understanding of which will be useful for developing a strategy for the search for new drugs that selectively disrupt the energy production of bacterial cells.

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Section: Mycobacterium Tuberculosis F 1 ∙...mentioning

confidence: 99%

F1·Fo ATP Synthase/ATPase: Contemporary View on Unidirectional Catalysis

Zharova

Grivennikova

Borisov

2023

IJMS

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“…The difficult-to-treat pathogen infections pose a significant threat to global health . Among these, tuberculosis (TB), particularly TB caused by multidrug-resistant Mycobacterium tuberculosis ( M. tb ; the causative agent of TB), stands out as one of the most highly contagious and lethal diseases. , In recent years, there have been 8.7 million newly increased cases of TB annually, resulting in 1.5 million deaths, thus emphasizing the urgent necessity for the discovery of effective drugs. , …”

Section: Introductionmentioning

confidence: 99%

“…3,4 In recent years, there have been 8.7 million newly increased cases of TB annually, resulting in 1.5 million deaths, thus emphasizing the urgent necessity for the discovery of effective drugs. 5,6 The development of peptide-based drugs offers a solution to this critical issue by harnessing the vast diversity of amino acid sequences, which endows peptides with exceptional structural and functional versatility. 7−10 Consequently, they hold great promise as an invaluable resource for drug discovery and development.…”

Section: Introductionmentioning

confidence: 99%

Assembly-Induced Membrane Selectivity of Artificial Model Peptides through Entropy–Enthalpy Competition

Wei,

Tu,

et al. 2024

ACS Nano

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Peptide design and drug development offer a promising solution for combating serious diseases or infections. In this study, using an AI−human negotiation approach, we have designed a class of minimal model peptides against tuberculosis (TB), among which K7W6 exhibits potent efficacy attributed to its assembly-induced function. Comprising lysine and tryptophan with an amphiphilic α-helical structure, the K7W6 sequence exhibits robust activity against various infectious bacteria causing TB (including clinically isolated and drug-resistant strains) both in vitro and in vivo. Moreover, it synergistically enhances the effectiveness of the first-line antibiotic rifampicin while displaying low potential for inducing drug resistance and minimal toxicity toward mammalian cells. Biophysical experiments and simulations elucidate that K7W6's exceptional performance can be ascribed to its highly selective and efficient membrane permeabilization activity induced by its distinctive self-assembly behavior. Additionally, these assemblies regulate the interplay between enthalpy and entropy during K7W6−membrane interaction, leading to the peptide's two-step mechanism of membrane interaction. These findings provide valuable insights into rational design principles for developing advanced peptide-based drugs while uncovering the functional role played by assembly.

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“…Several substituted THIQ analogs are described as anti‐tubercular agents [15–17] . Guo Liang's group reported a series of substituted THIQ derivatives as Mtb ATP synthase inhibitors under aerobic and anaerobic conditions.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Antimycobacterial Evaluation of Novel Tetrahydroisoquinoline Hydrazide Analogs

Kumar

Khetmalis

Nandikolla

et al. 2023

Chemistry & Biodiversity

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A series of novel 2-substituted-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carbohydrazide were designed, synthesized and structures were confirmed by analytical methods, viz., 1 H-NMR, 13 C-NMR and Mass spectrometry. Synthesized derivatives were evaluated for their anti-mycobacterial activity against Mycobacterium tuberculosis (Mtb) H37Ra. Among all the evaluated compounds, 10A25 containing biphenyl moiety exhibited significant inhibition with IC 50 4.7 μM. 10A19, with an electron-withdrawing Iodo group in the ortho position of the phenyl exhibited significant anti-tubercular activity with IC 50 8.8 μM. IC 50 values of the remaining compounds ranged from 9.2 to 73.6 μM. Molecular docking study of the significantly active compound 10A25 was performed to determine the putative binding position of the test ligand at the active site of the selected target proteins Mycobacterium tuberculosis enoyl reductase (InhA) PDB -4TZK and peptide deformylase PDB -3E3U. A suitable single crystal for one of the active compounds, 10A12, was generated and analysed to further confirm the structure of the compounds.

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Synthesis and structure-activity relationships for a new class of tetrahydronaphthalene amide inhibitors of Mycobacterium tuberculosis

Cited by 8 publications

References 23 publications

F1·Fo ATP Synthase/ATPase: Contemporary View on Unidirectional Catalysis

F1·Fo ATP Synthase/ATPase: Contemporary View on Unidirectional Catalysis

Assembly-Induced Membrane Selectivity of Artificial Model Peptides through Entropy–Enthalpy Competition

Design, Synthesis, and Antimycobacterial Evaluation of Novel Tetrahydroisoquinoline Hydrazide Analogs

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