BACKGROUND Enzyme promiscuity has attracted significant attention from chemists and biochemists in recent years. However, long reaction time and use of toxic organic solvents limit its applications for industrial processes. 1,4-Dihydropyridine (1,4-DHP) calcium antagonists are recommended for the first line treatment of hypertension. Although some chemical protocols for the preparation of 1,4-DHP calcium antagonists have been developed, enzymatic synthesis of these compounds still remains uncovered. RESULTS Solvent-free quick synthesis of 1,4-DHP calcium antagonists felodipine, nitrendipine, nifedipine and nemadipine B and their derivatives was achieved by Lipozyme (R) RM IM (triacylglycerol acylhydrolase, EC3.1.1.3)-catalyzed multicomponent reactions of aromatic aldehyde, alkyl acetoacetate and alkyl 3-aminocrotonate under ball-milling conditions. The products were obtained in moderate yields (up to 86.8%) and the influence of reaction conditions including catalyst loading, grinding auxiliary and grinding frequency was investigated. CONCLUSION The protocol successfully overcame some longstanding problems in the field of enzymatic promiscuity research, such as long reaction time and use of harmful organic solvents, and demonstrated the potential application value of promiscuous enzyme-catalyzed reactions under ball-milling conditions for pharmaceutical synthesis. (c) 2019 Society of Chemical Industry