A Facile Synthesis of 3-Substituted Coumarins and Investigation of Their 3CLpro Inhibition Activity Against SARS-CoV-2
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Choudhary, Manoj K.
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Bhabha Atom Res Ctr, Bioorgan Div, Mumbai 400085, India
Homi Bhabha Natl Inst, Mumbai 400094, IndiaBhabha Atom Res Ctr, Bioorgan Div, Mumbai 400085, India
Choudhary, Manoj K.
[1
,2
]
Ansari, Khalid
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Indian Inst Technol, Dept Phys, Roorkee 247667, IndiaBhabha Atom Res Ctr, Bioorgan Div, Mumbai 400085, India
Ansari, Khalid
[3
]
Junghare, Vivek
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Indian Inst Technol, Ctr Nanotechnol, Dept Biosci & Bioengn, Roorkee 247667, IndiaBhabha Atom Res Ctr, Bioorgan Div, Mumbai 400085, India
Junghare, Vivek
[4
]
Nayak, Sandip K.
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Bhabha Atom Res Ctr, Bioorgan Div, Mumbai 400085, IndiaBhabha Atom Res Ctr, Bioorgan Div, Mumbai 400085, India
Nayak, Sandip K.
[1
]
Hazra, Saugata
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Indian Inst Technol, Ctr Nanotechnol, Dept Biosci & Bioengn, Roorkee 247667, IndiaBhabha Atom Res Ctr, Bioorgan Div, Mumbai 400085, India
Hazra, Saugata
[4
]
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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
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.