Synthesis, Molecular Docking, DFT and Pharmacophore Studies of New Naphthalene-Heterocycle Hybrids of Prospective Antiviral Activity.

Abdelwahab, Mohamed; Mohamed, Ashraf M; Mahmoud, Salwa Faheem; Elnaggar, Dina Hamdy; Abde lHafez, Naglaa Abdelsamei; GabAllah, Mohamed; Abou-Amra, Eman S; Hussein, Ahmed M.

doi:10.21608/ejchem.2025.329489.10655

	Synthesis, Molecular Docking, DFT and Pharmacophore Studies of New Naphthalene-Heterocycle Hybrids of Prospective Antiviral Activity.
Egyptian Journal of Chemistry
Volume 68, Issue 6, June 2025, Page 43-66 PDF (1.97 MB)
Document Type: Original Article
DOI: 10.21608/ejchem.2025.329489.10655
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Authors
Mohamed Abdelwahab ¹; Ashraf M Mohamed ²; Salwa Faheem Mahmoud ³; Dina Hamdy Elnaggar⁴; Naglaa Abdelsamei Abde lHafez ¹; Mohamed GabAllah ⁵; Eman S Abou-Amra ⁶; Ahmed M. Hussein ⁷
¹Applied Organic Chemistry Department, National Research Centre, Dokki 12622, Cairo, Egypt
²Applied Organic Chemistry Department, National Research Centre, Dokki, Cairo, Egypt.
³Applied Organic Chemistry Department, National Research Centre, Dokki 12622, Cairo, Egypt .
⁴Applied Organic Chemistry Department, National Research Centre, Dokki 12622, Cairo, Egypt.
⁵Center of Scientific Excellence for Influenza Viruses, National Research Centre, El-Buhouth Street, Dokki, Cairo, 12622, Egypt
⁶Organic Chemistry Department, Faculty of Science, Al-Azhar University (Girls) Nasr City, 11751, Egypt.
⁷Chemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef 62511, Egypt
Abstract
The rate of anti-viral drugs resistance has increased dramatically even while there are fewer new antivirals available agents. The COVID-19 pandemic has highlighted the necessity of further endeavors to create comprehensive treatments to counteract SARS-CoV-2 infection. In the current study, an attempt to synthesize numerous N-heterocycles of substituted pyridine and pyrazole constituents have a marked family of molecules with a significant function in medicinal chemistry as promising possibilities for future antiviral drugs. Enaminones play a crucial role in the synthesis of diverse nitrogen-containing heterocyclic compounds. Heterocyclization of enaminone 2 with 6-amino-2-thioxopyrimidine-4-one 3 afforded the corresponding 2-thioxopyrido[2,3-d] pyrimidine-4-one derivative 5. Some new 1-aryl-3,4-disubstituted pyrazoles 8a-e were synthesized via the reaction of hydrazonoyl chloride derivatives 7a-e with enaminone 2. Pyrazolo[3,4-d] pyridazine derivative 9 was obtained through the hydrazinolysis of the new 1-aryl-3,4-disubstituted pyrazole derivative 8e. As well, malononitrile and 2,4-pentandione reacted with enaminone 2 to afford 6-naphthyl-2,3-disubstituted pyridines 10 and 11, respectively. Novel two pharmacophoric models of substituted [1,2,4]triazolo[1,5-a]pyrimidine 12 and [4,5]imidazolo[1,2-a]pyrimidine 13 were synthesized in good yield. Microanalytical data and elemental analysis have been used to prove the chemical structures of the new products. The antiviral activity of the new synthesized compounds was tested against VERO-E6 cell lines and compounds 8a, 8b and 8d exhibited good inhibition activities against SARS-COV 2 virus with selectivity index (SI) 21.98 and 27.73, respectively. Docking investigation of the designed structures has been studied into SARS-CoV-2 spike glycoprotein (PDB ID: 6VSB) and compounds 8b and 8d showed good fitting inside the binding site of the protein molecular surface with minimum binding energy. Additionally, we used density-functional theory (DFT) to examine the molecular geometry and structure of the more effective compounds to deduce their antiviral effects.
Keywords
Enaminone; triazolopyrimidine; pyrimidine-4-one; pyrazolopyridazine; hydrazonyl chloride; docking; antiviral


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