Synthesis and dihydrofolate reductase inhibitory activity of 2-amino-6-(arylaminomethyl) thieno[2,3-d]pyrimidin-4(3H)-ones

Abstract

The present work deals with synthesis and biological evaluation of novel compounds as potential inhibitors of dihydrofolate reductase (DHFR) from opportunistic microorganisms – Pneumocystis carinii (pc), Toxoplasma gondii (tg) and Mycobacterium avium (ma). A set of 6 lipophilic and 1 classical antifolates of thieno[2,3-d]pyrimidine series were designed and synthesised with key pharmacophoric features of DHFR inhibitors and aminomethylene bridge joining the aromatic part and 2-amino-4-oxothieno[2,3-d]pyrimidine nucleus. Investigation of the DHFR inhibitory activity of the synthesised compounds revealed that 2-amino-6-[(4-methoxyphenylamino)-, 6--[(4-chlorophenylamino)- and 6-[(2,5 ichlorophenylamino)methyl]thieno[2,3-d]pyrimidin-4(3H)- ones had a moderate activity (IC50 56.5, 49.9 and 23 μM, respectively) against pcDHFR. Activity of those compounds against tgDHFR (IC50 6.0, 2.8 and 2.3 μM, respectively) was comparable to that of trimethoprim (IC50 2.7 μM). No synthesised lipophilic antifolates showed activity towards maDHFR. The classical antifolate 2-{4-[(2-amino-4-oxo-3,4- dihydrothieno[2,3-d]pyrimidin-6-yl)methylamino]benzamido}-L-glutamic acid inhibited DHFRs from all microorganisms (IC50 6.6 μM for pcDHFR, 1.06 μM for tgDHFR and 16.9 μM for maDHFR).