Reinvestigation of the structure-activity relationships of isoniazid

Hegde, Pooja; Boshoff, Helena I.; Rusman, Yudi; Aragaw, Wassihun Wedajo; Salomon, Christine; Dick, Thomas; Aldrich, Courtney C.

doi:10.1016/j.tube.2021.102100

Cited by 8 publications

(8 citation statements)

References 44 publications

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“…In the case of the seco-azacubane-isoniazid epimer 31, loss in activity was observed, which was somewhat expected given the inability to access the desired target (i.e., 29) that more closely resembles the critical 1,4-substitution pattern of isoniazid (11). 28 In conclusion, the highly unusual seco-1-azacubane-2carboxylic acid (1) framework was successfully incorporated into a wider range of bioactive chemical templates using both traditional and solid-phase synthetic protocols. In terms of the latter, it is particularly noteworthy that the Fmoc-derivative (22) was successfully deployed under solid-phase conditions, which supports the use of noncanonical amino acids in drug discovery more generally.…”

Section: ■ Synthesismentioning

confidence: 93%

“…Although, the conformational changes imposed by 1 were clearly detrimental to ACE inhibition and MOP activity, they seem favorable for DOP activity (Figure B). In the case of the seco -azacubane-isoniazid epimer 31 , loss in activity was observed, which was somewhat expected given the inability to access the desired target (i.e., 29 ) that more closely resembles the critical 1,4-substitution pattern of isoniazid ( 11 ) …”

Section: Biological Evaluationmentioning

confidence: 95%

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seco-1-Azacubane-2-carboxylic Acid: Derivative Scope and Comparative Biological Evaluation

Kong,

Fahrenhorst-Jones,

Kuo

et al. 2023

J. Org. Chem.

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The unusual and sterically constrained amino acid, seco-1-azacubane-2-carboxylic acid, was incorporated into a range of bioactive chemical templates, including enalaprilat, perindoprilat, endomorphin-2 and isoniazid, and subjected to biological testing. The endomorphin-2 derivative displayed increased activity at the δ opioid receptor, but a loss in activity was observed in the other cases, although human normal cell line evaluation suggests limited cytotoxic effects.

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Section: ■ Synthesismentioning

confidence: 93%

Section: Biological Evaluationmentioning

confidence: 95%

seco-1-Azacubane-2-carboxylic Acid: Derivative Scope and Comparative Biological Evaluation

Kong,

Fahrenhorst-Jones,

Kuo

et al. 2023

J. Org. Chem.

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“…Further, the 1 H NMR spectra of cinnamamides 3a-j consistently showed a singlet at δ 10.08-10.62 and 10.75-10.89 ppm assigned to the two protons of the hydrazides. The 13 C NMR spectra of cinnamamides 3a-j showed two carbon signals at δ 164.0-164.5 ppm and 164.4-165.7 ppm that were assigned to the two carbons of the two hydrazides carbonyls [30]. The 1 H NMR spectra of cinnamamides 3k-n showed a singlet at δ 5.84-6.13 ppm which was assigned to the NH protons of the amide groups.…”

Section: Synthesis Of Cinnamamides 3a-nmentioning

confidence: 97%

Synthesis and α-glucosidase inhibitory activity of cinnnamamides

Aijijiyah

Wati

Rahayu

et al. 2022

Preprint

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Suitably substituted cinnnamamides were successfully synthesized in 11-92% yield. Majority of the cinnnamamides displayed IC50 greater than acarbose. Their α-glucosidase inhibitory activity greatly depended on their structure with electron-withdrawing groups on the cinnamoyl aromatic ring causing increased inhibition activity. The synthesized cinnnamamides showed acceptable physicochemical and pharmacokinetics characteristics with little toxicity indicating their potential use as lead drug candidates. Molecular docking studies of these compounds were also conducted to elucidate their mechanism of action. Overall, these cinnnamamides show potential as lead structures for further optimization as α-glucosidase inhibitors.

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“…Substitution of position 2 with a methyl group revealed antitubercular activity comparable to isoniazid (Figure 2). 10,11 Figure 2: Structure-activity relationship of isoniazid.…”

Section: Structure-activity Relationship Of Isoniazidmentioning

confidence: 99%

Isoniazid, Mechanism of action, Biological Activity, Resistance and Biotransformation

Badawy

Abouelsaoud

Kabbash

et al. 2023

Journal of Advanced Medical and Pharmaceutical Research

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Isoniazid is a synthetic antimicrobial and one of the most essential first-line drugs used in the treatment of tuberculosis. In addition, isoniazid has been used as a prophylactic drug for patients with latent Mycobacterium tuberculosis infection to prevent the reactivation of the disease. It is a prodrug that is activated by catalase-peroxidase (KatG) enzyme. Catalase peroxidase enzyme converts isoniazid to reactive species. Isoniazid reactive species inhibit enoyl acyl-carrier-protein reductase (InhA) enzyme, which is involved in the biosynthesis of fatty acids of mycobacteria. Isoniazid is metabolized by amidase enzyme into isonicotinic acid and hydrazine. Chronic toxicity of isoniazid results in hepatotoxicity and peripheral neuropathy. For active tuberculosis, isoniazid is often used together with rifampicin, pyrazinamide, and either streptomycin or ethambutol. Multiple extensively and totally drug-resistant strains of Mycobacterium tuberculosis were reported. Due to the development of Mycobacterium tuberculosis resistance to isoniazid, a continuous search for new drugs is a demand to combat this global problem.

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Reinvestigation of the structure-activity relationships of isoniazid

Cited by 8 publications

References 44 publications

seco-1-Azacubane-2-carboxylic Acid: Derivative Scope and Comparative Biological Evaluation

seco-1-Azacubane-2-carboxylic Acid: Derivative Scope and Comparative Biological Evaluation

Synthesis and α-glucosidase inhibitory activity of cinnnamamides

Isoniazid, Mechanism of action, Biological Activity, Resistance and Biotransformation

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