Investigation of thiophene derivatives as potential antihypertensive agents: DFT, molecular docking and ADMET studies

Despite significant advancements in the prevention, detection, and treatment of high blood pressure (BP), hypertension remains a major public health concern. With approximately 1.38 billion individuals affected worldwide, high BP is linked to high mortality and morbidity rates due to stroke, coronary heart disease, congestive heart failure (CHF), and end-stage renal disease, along with a detrimental impact on quality of life. However, medications to completely curtail hypertension are not yet available, but the risk can be reduced through lifestyle modification or a combination of medication and pharmacotherapy. Hence, in this context, we theoretically investigate the potency of the thiophene derivative 5-(4-bromo-5-(methylthio)thiophene-2-yl)-N-phenyl-1,3,4-thiadiazol-2-amine (3A, 3B, 3C, 3D, and 3E) via the ωB97XD/6-311 +  + G (2d, 3p) method of DFT. The compounds show promising stability and reactivity, as seen from their electronic properties and structural studies. The experimental FT-IR analysis and molecular electrostatic potential data reveal important functional groups at certain frequencies, underscoring the electrophilic and nucleophilic characteristics of these compounds. Interestingly, hypertensive target proteins such as 2VWI and 5D9H have strong binding affinities for compound 3a, at -6.4 kcal/mol and -6.3 kcal/mol, respectively. When aspirin was docked with 2VWI and 5D9H, the binding affinities were -3.8 kal/mol and -5.0 kal/mol, respectively. Therefore, thiophene derivatives, particularly 3A compounds, demonstrate strong efficacy in lowering blood pressure levels due to their unique binding affinity and conventional hydrogen bonding.

The online version contains supplementary material available at 10.1007/s40203-025-00441-2.