Abstract: Myeloperoxidase (MPO) is an important target for drug design because of its contributing role in many inflammatory syndromes such as atherosclerosis, rheumatoid arthritis, end-stage renal disease or neurodegeneration. Rational drug design assisted by virtual screening is an interesting tool to design new chemical entities that could inhibit MPO. After a high throughput virtual screening of a database, bis-2,2′-[(dihydro-1,3(2H,4H)-pyrimidinediyl)bis(methylene)]phenol was chosen as a starting hit and we used different strategies of chemical synthesis to perform pharmacomodulation described by the three following approaches: I) changing the position of the two nitrogen atoms in the hexahydropyrimidine cycle leading to piperazine derivatives, II) omitting one nitrogen atom in the hexahydropyrimidine leading to piperidine derivatives, III) opening the cycle of hexahydropyrimidine and keeping one nitrogen atom in the aliphatic chain leading to alkylamine derivatives. This led to 30 compounds that have been assessed in an in vitro inhibition MPO test. We found that the alkylamine compounds were active but to a lesser extent than the starting hit. Exception for propylamine derivatives with a phenyl cycle should be noticed. As indolic compounds have demonstrated interesting inhibiting properties, we combined indole ring with thephenolhydropyrimidine structure which led to compounds more active than the hit. Among them, propylamine derivatives were new MPO inhibitors with a nanomolar IC50. Kinetics studies for the most potent inhibitors were conducted and reflected a fast reaction with compound I (MPO-Porphyrin•+-Fe(IV)=O) resulting in the accumulation of compound II (MPO-Porphyrin-Fe(IV)=O). Structure-activity relationship will be discussed to highlight the chemical group of interest in the interaction with MPO.