Abstract: Hypertension is a leading modifiable risk factor for cardiovascular disease, and angiotensin-converting enzyme (ACE) is an established therapeutic target. This study reports the drug design, synthesis, characterization, in-silico docking and in-vitro ACE-inhibitory evaluation of -1,3-thiazinan-4-one derivatives (5a–5e). The compounds were prepared in 68–75% yield by a one-pot, solvent-free Staudinger/aza-Wittig sequence in which benzyl azide, triethyl phosphite, a substituted aromatic aldehyde and 3-mercaptopropionic acid were heated at 140–150 °C for 10–20 min. Purity was supported by single-spot TLC (Rf 0.45–0.65; hexane: ethyl acetate, 4:1) and melting points of 120–140 °C, and the products were characterized by FT-IR and 1H NMR spectroscopy. In-silico analysis showed that four compounds satisfied all Lipinski criteria. Molecular docking against human ACE gave binding energies of −7.5 to −8.4 kcal/mol, with the thiophene derivative 5c (−8.4 kcal/mol) and the 4-nitrophenyl derivative 5d (−8.3 kcal/mol) ranking highest. In the in-vitro hippuryl-histidyl-leucine (HHL) assay, 5c and 5d inhibited ACE by 75.21 ± 4.25% and 71.48 ± 4.19% at 100 mg/mL, compared with 79.35 ± 4.84% for captopril; the IC50 values recorded for 5c, 5d and captopril were 10.377, 20.431 and 5.808 mg/mL, respectively. These findings identify the 1,3-thiazinan-4-one scaffold, particularly 5c, as a promising starting point for ACE-directed antihypertensive.