Potential application of bisoprolol derivative compounds as antihypertensive drugs: synthesis and in silico study

Abstract

Two bisoprolol derivatives, N-acetyl bisoprolol and N-formyl bisoprolol, belonging to the beta-blocker class of antihypertensive drugs, were synthesized using acetylation and formylation reactions. The yields of the reactions were determined to be 32.40% for N-acetyl bisoprolol and 20.20% for N-formyl bisoprolol. In silico methods such as molecular docking, molecular dynamics simulation and SwissADME prediction were employed to evaluate the potential of these bisoprolol derivatives as antihypertensive drugs. These methods were used to assess the interaction between the bisoprolol derivatives and various receptors associated with hypertension, including human angiotensin I-converting enzyme (PDB ID: 1O8A), renin (PDB ID: 2V0Z), beta-1 adrenergic receptors (PDB ID: 4BVN, 7BVQ), voltage-dependent L-type calcium channel subunit alpha-1S (PDB ID: 6JP5) and mineralocorticoid receptor (PDB ID: 6L88). Our results demonstrated the highest binding energy when bisoprolol and its derivatives bound to 4BVN, with binding energy values of 6.74 kcal mol^-1, 7.03 kcal mol^-1 and 7.63 kcal mol^-1 for bisoprolol, N-acetyl bisoprolol and N-formyl bisoprolol, respectively. The stability of these complexes was confirmed by molecular dynamics simulations, with a root-mean-square deviation value of approximately 2. Furthermore, the SwissADME results indicated that both derivatives exhibited similar properties to the reference drug bisoprolol.

Keywords: antihypertensives; bisoprolol; derivative; molecular docking; organic synthesis.

Figure 1.

Binding energy of bisoprolol (compound 1, blue), N-acetyl bisoprolol (compound 3, yellow) and N-formyl bisoprolol (compound 5, green) with six target proteins through molecular docking simulations.

Figure 2.

Visualization of complexes formed between: (a) N-formyl bisoprolol and 1O8A, (b) N-acetyl bisoprolol and 2V0Z, (c) N-formyl bisoprolol and 4BVN, (d) N-formyl bisoprolol and 6JP5, (e) N-acetyl bisoprolol and 6L88, and (f) N-formyl bisoprolol and 7BVQ.

Figure 3.

Reaction scheme for the synthesis of the N-acetyl bisoprolol compound.

Figure 4.

Reaction scheme for the synthesis of the N-formyl bisoprolol compound.

Figure 5.

(a) RMSD of the 4BVN complex backbone, (b) RMSD of the 4BVN complex ligand, (c) number of hydrogen bonds in the 4BVN complex, and (d) RMSF of the 4BVN complex. Colour code: black for bisoprolol (compound 1), red for N-acetyl bisoprolol (compound 3) and blue for N-formyl bisoprolol (compound 5).