Synthesis, X-ray diffraction, and computational studies of acyclovir and HBG analogs derived from Triazolyl-1,4-benzothiazine and their oxidized forms for breast cancer and SARS-CoV-2.

This study presents a simple and efficient synthetic method for preparing a new series of acyclonucleosides derived from 1,4-benzothiazine and 1,4-benzothiazine-1,1-dioxide. These compounds feature the introduction of a 1,2,3-triazole-4-ylmethyl ring as a spacer between the heterocyclic bases and the pseudosugars of acyclovir (ACV) and hydroxybutylguanine (HBG). The acyclonucleosides were synthesized through copper-catalyzed 1,3-dipolar cycloaddition reactions between azides 8a and 8b and the N4-propargyl base 7. Following this, the deprotection of the acyclic chains and the oxidation of the sulfur to sulfone afforded the acyclonucleosides 9a,b-12a,b in satisfactory yields. The synthesized acyclonucleosides were characterized using 1H and 13C NMR spectroscopy. Moreover, the structure of 9b was confirmed by single-crystal X-ray diffraction analysis. The synthesized acyclonucleosides were evaluated through in silico studies, including network pharmacology for bioactivity, toxicity prediction, physicochemical properties, and ADMET analysis. Molecular docking studies revealed significant interactions, highlighting compound 11b's favorable binding with the target protein AKT1, achieving a binding energy of -6.43 kcal/mol, which is close to the Capivasertib standard. Similarly, compound 12b showed interactions akin to hydroxychloroquine, with a binding energy of -6.29 kcal/mol for the SARS-CoV-2 target protein. Molecular dynamics simulations further validated the stability of the ligand-protein complexes during 200 ns, as evidenced by acceptable RMSD and RMSF and Rg values. The post-dynamic, MMGBSA, PCA, FEL, PDF, and DCCM analyses of the AKT and SARS-CoV-2 protein-ligand complexes have provided comprehensive insights into their interactions with standard drugs, binding affinities, conformational dynamics, and structural stability. These studies are crucial for understanding the molecular mechanisms underlying drug efficacy and resistance, thereby informing the rational design of new inhibitors targeting AKT and SARS-CoV-2 proteins. Finally, the two most promising compounds, 11b and 12b, selected from the docking results, were analyzed using Density Functional Theory (DFT). These analyses revealed significant variations in their electronic properties, providing valuable insights into their reactivity, stability, and polarity.