New fused tetracyclic ring systems: synthesis of 1-thia-4a,11,12-triazatetracenes via a multicomponent strategy, 2D-HMBC structural confirmation, and antimicrobial activity

Abstract

We report a novel synthetic strategy for tetracyclic heterocycles, specifically 1-thia-4a,11,12-triazatetracenes, representing a previously unreported fused ring system, using enamine 8-amino-3,4-dihydropyrimido[2,1-b][1,3]thiazin-6-one as a versatile building block. This enamine undergoes multicomponent reactions with aldehydes and dimedone in refluxing acetic acid, efficiently affording the target fused heterocycles. Structural elucidation was confirmed via alternative synthetic routes and 2D-HMBC correlations. The resulting compounds possess a rigid, planar, and highly conjugated tetracyclic framework enriched with heteroatoms (N, S, O), features known to enhance binding interactions with biological macromolecules. Such structural characteristics favor interactions within enzyme active sites, particularly nucleic acid–processing enzymes such as DNA-directed RNA polymerase, as a putative target based on molecular docking predictions. Among the synthesized series, compound 9a emerged as a potent broad-spectrum agent, demonstrating strong antibacterial activity against all tested strains, with notable efficacy against S. aureus (MIC = 0.5 mg mL⁻¹). Molecular docking studies corroborated its bioactivity, predicting higher binding affinity of 9a against Aspergillus terreus (ΔG = −9.2 kcal mol⁻¹) compared to fluconazole, and stronger predicted affinity against the bacterial target than tetracycline (ΔG = −6.7 kcal mol⁻¹). These results position 9a as a promising lead for further antimicrobial development.