Targeting species specific amino acid residues: Design, synthesis and biological evaluation of 6-substituted pyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors and potential anti-opportunistic infection agents
dc.contributor.author | Shah, Khushbu | |
dc.contributor.author | Lin, Xin | |
dc.contributor.author | Queener, Sherry F. | |
dc.contributor.author | Cody, Vivian | |
dc.contributor.author | Pace, Jim | |
dc.contributor.author | Gangjee, Aleem | |
dc.contributor.department | Pharmacology and Toxicology, School of Medicine | en_US |
dc.date.accessioned | 2019-08-09T19:26:02Z | |
dc.date.available | 2019-08-09T19:26:02Z | |
dc.date.issued | 2018-05-15 | |
dc.description.abstract | 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. | en_US |
dc.eprint.version | Author's manuscript | en_US |
dc.identifier.citation | Shah, K., Lin, X., Queener, S. F., Cody, V., Pace, J., & Gangjee, A. (2018). Targeting species specific amino acid residues: Design, synthesis and biological evaluation of 6-substituted pyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors and potential anti-opportunistic infection agents. Bioorganic & medicinal chemistry, 26(9), 2640–2650. doi:10.1016/j.bmc.2018.04.032 | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/20328 | |
dc.language.iso | en_US | en_US |
dc.publisher | Elsevier | en_US |
dc.relation.isversionof | 10.1016/j.bmc.2018.04.032 | en_US |
dc.relation.journal | Bioorganic & Medicinal Chemistry | en_US |
dc.rights | Publisher Policy | en_US |
dc.source | PMC | en_US |
dc.subject | DHFR inhibitors | en_US |
dc.subject | Opportunistic infections | en_US |
dc.subject | Pneumocystis pneumonia | en_US |
dc.subject | Pyrrolo[2,3-d]pyrimidines | en_US |
dc.subject | hDHFR | en_US |
dc.subject | pjDHFR | en_US |
dc.title | Targeting species specific amino acid residues: Design, synthesis and biological evaluation of 6-substituted pyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors and potential anti-opportunistic infection agents | en_US |
dc.type | Article | en_US |