Synthesis, characterization, and computational study of s-methylthio- and n-methylamine substituted epoxybenzo[7,8]oxocyno[4,3-b]pyridine derivatives
Stalinskaya A.L. Pustolaikina I.A. Kurmanova A.F. Rakhimzhanova A.S. Muzaparov R.A. Normatov S. Novikov A.S. Kulakov I.V.
25 December 2025Elsevier B.V.
Journal of Molecular Structure
2025#1348
Background: Natural integrastatins and their synthetic derivatives with the oxocine ring exhibit a wide range of antiviral activities, including activities against HIV-1 and SARS-CoV-2 viruses, which makes these compounds interesting for pharmaceutical purposes. Objectives: A series of novel derivatives of 9-methyl-substituted epoxybenzo[7,8]oxocino[4,3-b]pyridine were synthesized, characterized and studied for antiviral activity using an in silico approach. Methodology: Synthesis was carried out based on 3,5-diacetyl-2,6-dimethylpyridine and S-methylthio- and N-methylamino derivatives of salicylic aldehyde. The structure of the newly synthesized compounds was confirmed by 1H and 13C NMR, chromato-mass spectrometry, and elemental analysis. Their physicochemical properties and antiviral potential were studied using DFT B3LYP/6–311++G(d,p) CPCM (water) calculations, molecular docking, and molecular dynamics simulations. Results: As a result of the study, optimal synthesis parameters (solvent, reaction time, amount and type of acid catalyst, temperature, etc.) were selected for each of the nine novel 9-methyl-substituted epoxybenzo[7,8]oxocino[4,3-b]pyridine derivatives, ensuring good yields. Using an in silico approach, antiviral activity towards viral proteins of human rhinovirus 14, HIV-1 integrase, SARS-CoV-2 RNA-dependent polymerase was predicted and evaluated for all derivatives. Compound 6i from the series of newly synthesized derivatives was selected as the best one because it demonstrated excellent binding affinity to HIV-1 protein and high stability of the protein-ligand complex. However, in silico evaluation of ADMET properties revealed that compound 6i was the least favorable candidate due to its limited absorption, high predicted toxicity, and poor metabolic stability. In contrast, compounds 6b, 6d, and 6 g demonstrated the most promising ADMET profiles, characterized by moderate clearance rates, low toxicity potential, and favorable metabolic stability.
3,5-diacetyl-2,6-dimethylpyridine , Alkaloids , Antiviral activity , Biologically active amines , Computational study , In silico , Integrastatins , Intramolecular cyclization , Molecular docking , Tetracyclic epoxybenzooxocine
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School of Natural Sciences, Tyumen State University, Perekopskaya str., 15a, Tyumen, 625003, Russian Federation
Department of Physical and Analytical Chemistry, Karaganda Buketov University, Universitetskaya str., 28, Karaganda, 100024, Kazakhstan
Infochemistry Scientific Center, ITMO University, Lomonosov str., 9, Saint Petersburg, 191002, Russian Federation
Institute of Chemistry, Saint Petersburg State University, Universitetskaya nab., 7/9, Saint Petersburg, 199034, Russian Federation
Research Institute of Chemistry, Рeoples’ Friendship University of Russia (RUDN University), Miklukho-Maklaya str., 6, Moscow, 117198, Russian Federation
School of Natural Sciences
Department of Physical and Analytical Chemistry
Infochemistry Scientific Center
Institute of Chemistry
Research Institute of Chemistry
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