Targeting Species Specific Amino Acid Residues: Design Synthesis and Biological Evaluation of 6-Substituted Pyrrolo23-dpyrimidines as Dihydrofolate Reductase Inhibitors and Potential Anti-Opportunistic Infection Agents

摘要

To combine the potency of trimetrexate (TMQ) or piritrexim (PTX) with the species selectivity of trimethoprim (TMP), target based design was carried out with the X-ray crystal structure of human dihydrofolate reductase (hDHFR) and the homology model of Pneumocystis jirovecii DHFR (pjDHFR). Using variation of amino acids such as Met33/Phe31 (in pjDHFR/hDHFR) that affect the binding of inhibitors due to their distinct positive or negative steric effect at the active binding site of the inhibitor, we designed a series of substituted-pyrrolo[2,3-d]pyrimidines. The best analogs displayed better potency (IC50) than PTX and high selectivity for pjDHFR versus hDHFR, with >4 exhibiting a selectivity for pjDHFR of 24-fold.