An approximation to the mechanism of inhibition of cystein proteases: nucleophilic sulphur addition to Michael acceptors type compounds

Kunakbaeva, Zulfia; Carrasco, Ramón; Rozas, Isabel

doi:10.1016/s0166-1280(03)00086-1

Cited by 15 publications

(15 citation statements)

References 24 publications

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“…The core structural features thought to be responsible for the observed antimalarial activity of 8b and 12 , and which were therefore to be retained in the analogs, were identified as the chloroquinoline moiety and either the phenyl-butenone moiety (for 12 ) or the chalcone moiety (for 8b ) (Figure 1) - the chloroquinoline moiety for its role in inhibition of hemozoin formation, 17 and the chalcone and phenyl-butenone moieties for their possible dual roles in malarial cysteine protease inhibition 18 and facilitating inhibition of hemozoin formation through π-π stacking interactions.…”

Section: Introductionmentioning

confidence: 99%

Enone– and Chalcone–Chloroquinoline Hybrid Analogues: In Silico Guided Design, Synthesis, Antiplasmodial Activity, in Vitro Metabolism, and Mechanistic Studies

et al. 2011

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Analogs of the previously reported antimalarial hybrid compounds 8b and 12 were proposed with the aim of identifying compounds with improved solubility and retained antimalarial potency. In silico characterization predicted improved solubilities of the analogs, particularly at low pH; they retained acceptable predicted permeability properties, but were predicted to be susceptible to hepatic metabolism. These analogs were synthesized and found to exhibit notable in vitro antimalarial activity. Compounds 25 and 27 were the most active of the analogs. In vitro metabolism studies indicated susceptibility of the analogs to hepatic metabolism. There was also evidence of primary glucuronidation for analogs 24 – 27. Presumed cis - trans isomerism of 12, 22 and 23 under in vitro metabolism assay conditions was also observed, with differences in the nature and rates of metabolism observed between isomers. Biochemical studies strongly suggested that inhibition of hemozoin formation is the primary mechanism of action of these analogs.

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Section: Introductionmentioning

confidence: 99%

Enone– and Chalcone–Chloroquinoline Hybrid Analogues: In Silico Guided Design, Synthesis, Antiplasmodial Activity, in Vitro Metabolism, and Mechanistic Studies

et al. 2011

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“…Earlier theoretical investigations [16,17] predict that the reaction of a thiolate with a Michael system leads to quite stable covalent bonds between the thiolate and the a,b-unsaturated carbonyl moiety. Thus, they predict an irreversible inhibition of thiol-containing enzymes by inhibitors containing such electrophiles as warheads.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Study of the Reaction of Thiol‐Containing Enzymes with α,β‐Unsaturated Carbonyl Substrates by Computation and Chemoassays

Paasche¹,

Schiller²,

Schirmeister³

et al. 2010

ChemMedChem

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We investigated the reactions between substituted alpha,beta-unsaturated carbonyl compounds (Michael systems) and thiols by computations as well as chemoassays. The results give insight into variations in the underlying mechanisms as a function of the substitution pattern. This is of interest for the mechanisms of inhibition of the SARS coronavirus main protease (SARS-CoV M(pro)) by etacrynic acid derivatives as well as for the excess toxicity of substituted alpha,beta-unsaturated carbonyl compounds. This study compares possible reaction courses including 1,4-addition followed by a ketonization step, and underscores the importance of a base-catalyzed step for the reactivity of thiol groups in enzymes. Phenyl and methyl substituents at the Michael system decrease the reactivity of the electrophilic compound, but chlorophenyl substituents partly recover the reactivity. Computations also indicate that electron-pushing substituents lead to a change in the reaction mechanism. The conformation of the Michael system is also found to significantly influence reactivity: the s-cis conformation leads to higher reactivity than the s-trans conformation. The computed data explain the trends in measured inhibition potencies of substituted alpha,beta-unsaturated carbonyl compounds and of reaction rates in chemical assays. They also indicate that the reversibility of inhibition does not stand in contrast to the formation of a new covalent bond between inhibitor and protease.

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“…balansain I, macrodontain I in Bromeliaceae7, 8 and araujiain in Asclepiadaceae 9. Cysteine proteases are proteolytic enzymes that act via nucleophilic attack of the sulfide anion, in the active site, to the peptide bond 10. Cysteine proteases have been implicated in the defensive system of plants against herbivorous insects11 and are thought to be involved in oxidative stress‐induced soybean programmed cell death 12.…”

Section: Introductionmentioning

confidence: 99%

Purification and properties of cysteine protease from rhizomes of Curcuma longa (Linn.)

Radhakrishnan

Balasubramanian

2009

J. Sci. Food Agric.

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An approximation to the mechanism of inhibition of cystein proteases: nucleophilic sulphur addition to Michael acceptors type compounds

Cited by 15 publications

References 24 publications

Enone– and Chalcone–Chloroquinoline Hybrid Analogues: In Silico Guided Design, Synthesis, Antiplasmodial Activity, in Vitro Metabolism, and Mechanistic Studies

Enone– and Chalcone–Chloroquinoline Hybrid Analogues: In Silico Guided Design, Synthesis, Antiplasmodial Activity, in Vitro Metabolism, and Mechanistic Studies

Mechanistic Study of the Reaction of Thiol‐Containing Enzymes with α,β‐Unsaturated Carbonyl Substrates by Computation and Chemoassays

Purification and properties of cysteine protease from rhizomes of Curcuma longa (Linn.)

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