Hydroxamate and thiosemicarbazone: Two highly promising scaffolds for the development of SARS-CoV-2 antivirals

Xu, Yin-Sui; Chigan, Jia-Zhu; Li, Jiaqi; Ding, Huan‐Huan; Sun, Le-Yun; Liu, Lu; Hu, Zhenxin; Yang, Ke‐Wu

doi:10.1016/j.bioorg.2022.105799

Cited by 8 publications

(3 citation statements)

References 55 publications

(74 reference statements)

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“…Thiosemicarbazone derivatives were recently reported as reversible inhibitors of SARS-CoV-2 M pro . [41] Compounds 58 and 119 possess electrophilic sites (CN and α,β-unsaturated C═C) that could suffer nucleophilic attack by the cysteine residue of M pro . The probability (p) values obtained through consensus calculations according to the MolDock Score and Plants Score algorithms can be found in Table 3 and Supporting Information: Tables S2-S4 with a complete description of the energy values for the two algorithms under study.…”

Section: K I Determination and Control Experimentsmentioning

confidence: 99%

Inhibitory effects of 190 compounds against SARS‐CoV‐2 M^pr^o protein: Molecular docking interactions

Souza

Sens

Hammerschmidt

et al. 2023

Archiv der Pharmazie

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COVID-19 has caused many deaths since the first outbreak in 2019. The burden on healthcare systems around the world has been reduced by the success of vaccines.However, population adherence and the occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are still challenging tasks to be affronted. In addition, the newly approved drug presents some limitations in terms of side effects and drug interference, highlighting the importance of searching for new antiviral agents against SARS-CoV-2. The SARS-CoV-2 main protease (M pro ) represents a versatile target to search for new drug candidates due to its essential role in proteolytic activities responsible for the virus replication. In this work, a series of 190 compounds, composed of 27 natural ones and 163 synthetic compounds, were screened in vitro for their inhibitory effects against SARS-CoV-2 M pro . Twentyfive compounds inhibited M pro with inhibitory constant values (K i ) between 23.2 and 241 µM. Among them, a thiosemicarbazone derivative was the most active compound. Molecular docking studies using Protein Data Bank ID 5RG1, 5RG2, and 5RG3 crystal structures of M pro revealed important interactions identified as hydrophobic, hydrogen bonding and steric interactions with amino acid residues in the active site cavity. Overall, our findings indicate the described thiosemicarbazones as good candidates to be further explored to develop antiviral leads against SARS-CoV-2. Moreover, the studies showed the importance of careful evaluation of test results to detect and exclude false-positive findings.

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Section: K I Determination and Control Experimentsmentioning

confidence: 99%

Inhibitory effects of 190 compounds against SARS‐CoV‐2 M^pr^o protein: Molecular docking interactions

Souza

Sens

Hammerschmidt

et al. 2023

Archiv der Pharmazie

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“…33 Jump dilution assays were applied to determine that benzophenone thiosemicarbazones are reversible inhibitors of human cathepsin L 34 and M Pro from SARS-CoV-2. 35 Reversible covalent inhibitors may have an improved safety profile in comparison to irreversible ones 36 so characterizing the reversibility is of utmost relevance. This may be especially true for cruzain, as the trials of the most promising inhibitor, the irreversible covalent vinyl sulfone K777, were stopped in preclinical trials due to safety concerns.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Inhibitors based on thiosemicarbazones were also suggested to be reversible inhibitors of the cysteine protease CPB of Leishmania mexicana . Jump dilution assays were applied to determine that benzophenone thiosemicarbazones are reversible inhibitors of human cathepsin L and M Pro from SARS-CoV-2 . Reversible covalent inhibitors may have an improved safety profile in comparison to irreversible ones so characterizing the reversibility is of utmost relevance.…”

Section: Introductionmentioning

confidence: 99%

Experimental and Computational Study of Aryl-thiosemicarbazones Inhibiting Cruzain Reveals Reversible Inhibition and a Stepwise Mechanism

Martins

Oliveira

Lameira

et al. 2023

J. Chem. Inf. Model.

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Trypanosoma cruzi is a parasite that infects about 6–7 million people worldwide, mostly in Latin America, causing Chagas disease. Cruzain, the main cysteine protease of T. cruzi, is a validated target for developing drug candidates for Chagas disease. Thiosemicarbazones are one of the most relevant warheads used in covalent inhibitors targeting cruzain. Despite its relevance, the mechanism of inhibition of cruzain by thiosemicarbazones is unknown. Here, we combined experiments and simulations to unveil the covalent inhibition mechanism of cruzain by a thiosemicarbazone-based inhibitor (compound 1). Additionally, we studied a semicarbazone (compound 2), which is structurally similar to compound 1 but does not inhibit cruzain. Assays confirmed the reversibility of inhibition by compound 1 and suggested a two-step mechanism of inhibition. The K i was estimated to be 36.3 μM and K i* to be 11.5 μM, suggesting the pre-covalent complex to be relevant for inhibition. Molecular dynamics simulations of compounds 1 and 2 with cruzain were used to propose putative binding modes for the ligands. One-dimensional (1D) quantum mechanics/molecular mechanics (QM/MM) potential of mean force (PMF) and gas-phase energies showed that the attack of Cys25-S– on the CS or CO bond yields a more stable intermediate than the attack on the CN bond of the thiosemicarbazone/semicarbazone. Two-dimensional (2D) QM/MM PMF revealed a putative reaction mechanism for compound 1, involving the proton transfer to the ligand, followed by the Cys25-S– attack at CS. The ΔG and energy barrier were estimated to be −1.4 and 11.7 kcal/mol, respectively. Overall, our results shed light on the inhibition mechanism of cruzain by thiosemicarbazones.

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Oxamic acid thiohydrazides and hydrazones based on them as convenient starting compounds for the synthesis of S- and N-containing heterocyclic products. A mini-review

Krayushkin,

Yarovenko

2024

Arabian Journal of Chemistry

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Hydroxamate and thiosemicarbazone: Two highly promising scaffolds for the development of SARS-CoV-2 antivirals

Cited by 8 publications

References 55 publications

Inhibitory effects of 190 compounds against SARS‐CoV‐2 M^pr^o protein: Molecular docking interactions

Inhibitory effects of 190 compounds against SARS‐CoV‐2 M^pr^o protein: Molecular docking interactions

Experimental and Computational Study of Aryl-thiosemicarbazones Inhibiting Cruzain Reveals Reversible Inhibition and a Stepwise Mechanism

Oxamic acid thiohydrazides and hydrazones based on them as convenient starting compounds for the synthesis of S- and N-containing heterocyclic products. A mini-review

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Hydroxamate and thiosemicarbazone: Two highly promising scaffolds for the development of SARS-CoV-2 antivirals

Cited by 8 publications

References 55 publications

Inhibitory effects of 190 compounds against SARS‐CoV‐2 Mpro protein: Molecular docking interactions

Inhibitory effects of 190 compounds against SARS‐CoV‐2 Mpro protein: Molecular docking interactions

Experimental and Computational Study of Aryl-thiosemicarbazones Inhibiting Cruzain Reveals Reversible Inhibition and a Stepwise Mechanism

Oxamic acid thiohydrazides and hydrazones based on them as convenient starting compounds for the synthesis of S- and N-containing heterocyclic products. A mini-review

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Inhibitory effects of 190 compounds against SARS‐CoV‐2 M^pr^o protein: Molecular docking interactions

Inhibitory effects of 190 compounds against SARS‐CoV‐2 M^pr^o protein: Molecular docking interactions