A Facile Synthesis of 3-Substituted Coumarins and Investigation of Their 3CLpro Inhibition Activity Against SARS-CoV-2

被引:0
作者
Choudhary, Manoj K. [1 ,2 ]
Ansari, Khalid [3 ]
Junghare, Vivek [4 ]
Nayak, Sandip K. [1 ]
Hazra, Saugata [4 ]
Mula, Soumyaditya [1 ,2 ]
机构
[1] Bhabha Atom Res Ctr, Bioorgan Div, Mumbai 400085, India
[2] Homi Bhabha Natl Inst, Mumbai 400094, India
[3] Indian Inst Technol, Dept Phys, Roorkee 247667, India
[4] Indian Inst Technol, Ctr Nanotechnol, Dept Biosci & Bioengn, Roorkee 247667, India
来源
CHEMISTRYOPEN | 2024年
关键词
Coumarins; Morita-Baylis-Hillman adducts; Friedel-Crafts alkylation; 3CLpro Inhibitors; SARS-CoV-2; Molecular Dynamics simulation; ADMET study; BAYLIS-HILLMAN REACTION; DRUG DISCOVERY; PREDICTION; SOLUBILITY; ABSORPTION; CHEMISTRY; BIOAVAILABILITY; DERIVATIVES; PROPERTY; EXTRACT;
D O I
10.1002/open.202400319
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The major threat to public health due to the outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been recognised as a global issue. The increase in morbidity is primarily due to the lack of SARS-CoV-2 specific drugs. One of the major strategies to combat this threat is to deactivate the enzymes responsible for the replication of corona virus. To this end, 3-arylidene/3-hydroxycoumarin induced deactivation of 3-chymotrypsin like protease (3CLpro) enzyme, which takes the pivotal role in the replication and maturation, was investigated. For ready availability of the compounds for the above investigation, we have developed a user-friendly protocol for the synthesis 3-hydroxycoumarin derivatives from cheap and readily available starting materials in two steps; i) Bronsted acid catalysed Friedel-Crafts alkylation of phenols with Morita-Baylis-Hillman adducts followed by intramolecular lactonization to trans-3-arylidenechroman-2-ones in one-pot and ii) ozonolysis in reasonably good yields. Pharmacokinetic assessments of coumarin derivatives revealed drug-like characteristics with moderate or low toxicity values. Notably, these hydroxycoumarins exhibited enhanced binding affinity against the 3CL protease of SARS-CoV-2, fitting well into the binding pocket akin to the previously studied inhibitor N3. Furthermore, a molecular dynamics study elucidated the dynamic behaviour of these small molecules when bound to the protein, showcasing intriguing complexities within the active site. Despite backbone variations and residual fluctuations, compounds 3 d-f and 6 a exhibited a consistent behaviour, instilling confidence in the therapeutic potential of these coumarins for combating SARS-CoV-2.
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页数:16
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共 81 条
  • [1] Revisiting the General Solubility Equation: In Silico Prediction of Aqueous Solubility Incorporating the Effect of Topographical Polar Surface Area
    Ali, Jogoth
    Camilleri, Patrick
    Brown, Marc B.
    Hutt, Andrew J.
    Kirton, Stewart B.
    [J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2012, 52 (02) : 420 - 428
  • [2] [Anonymous], Jmol: an open-source Java viewer for chemical structures in 3D
  • [3] [Anonymous], H. DeWinterSILICOS-IT Filter-It
  • [4] Antioxidant properties of 3-hydroxycoumarin derivatives
    Bailly, F
    Maurin, C
    Teissier, E
    Vezin, H
    Cotelle, P
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY, 2004, 12 (21) : 5611 - 5618
  • [5] The Baylis-Hillman reaction: a new continent in organic chemistry - our philosophy, vision and over three decades of research
    Basavaiah, Deevi
    Naganaboina, Ram Tilak
    [J]. NEW JOURNAL OF CHEMISTRY, 2018, 42 (17) : 14036 - 14066
  • [6] Less reactive ketones as electrophiles and acrylamides as activated alkenes in intramolecular Baylis-Hillman reaction: facile synthesis of functionalized γ-lactam frameworks
    Basavaiah, Deevi
    Reddy, Guddeti Chandrashekar
    Bharadwaj, Kishor Chandra
    [J]. TETRAHEDRON, 2014, 70 (43) : 7991 - 7995
  • [7] Design, synthesis and anticancer activities of stilbene-coumarin hybrid compounds: Identification of novel proapoptotic agents
    Belluti, Federica
    Fontana, Gabriele
    Dal Bo, Laura
    Carenini, Nives
    Giommarelli, Chiara
    Zunino, Franco
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY, 2010, 18 (10) : 3543 - 3550
  • [8] Bhadwaj K. C., 2016, Tetrahedron, V72, P312
  • [9] Inhibitory property of Piper betel extract against photosensitization-induced damages to lipids and proteins
    Bhattacharya, S.
    Mula, S.
    Gamre, S.
    Kamat, J. P.
    Bandyopadhyay, S. K.
    Chattopadhyay, S.
    [J]. FOOD CHEMISTRY, 2007, 100 (04) : 1474 - 1480
  • [10] ccp4, ABOUT US