Design, Synthesis, and Anti‐HIV‐1 Evaluation of a Novel Series of 1,2,3,4‐Tetrahydropyrimidine‐5‐Carboxylic Acid Derivatives

A series of tetrahydropyrimidine derivatives (2a – 2l) were designed, synthesized, and screened for anti‐HIV‐1 properties based on the structures of HIV‐1 gp41 binding site inhibitors, NB‐2 and NB‐64. A computational study was performed to predict the pharmacodynamics, pharmacokinetics, and drug‐likeness features of the studied molecules. Docking studies revealed that the carboxylic acid group in the molecules forms salt bridges with either Lys574 or Arg579. Physiochemical properties (e.g., molecular weight, number of hydrogen bond donors, number of hydrogen bond acceptors, and number of rotatable bonds) of the synthesized compounds confirmed and exhibited that these compounds were within the range set by Lipinski's rule of five. Compounds 2e and 2k with 4‐chlorophenyl substituent and 4‐methylphenyl group at C(4) position of the tetrahydropyrimidine ring was the most potent one among the tested compounds. This suggests that these compounds may serve as leads for development of novel small‐molecule HIV‐1 inhibitors.