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Plasmodium falciparum dihydrofolate reductase is an important target for antimalarial chemotherapy. The emergence of resistance has signifcantly reduced the effcacy of the classic antifolate drugs cycloguanil and pyrimethamine. In this paper we report new dihydrofolate reductase inhibitors identifed using molecular modelling principles with the goal of designing new antifolate agents active against both wild and tetramutant dihydrofolate reductase strains three series of trimethoprim analogues were designed, synthesised and tested for biological activity. Pyrimethamine and cycloguanil have been reported to loose effcacy because of steric repulsion in the active site pocket produced due to mutation in Plasmodium falciparum dihydrofolate reductase. The synthesised molecules have suffcient fexibility to withstand this steric repulsion to counteract the resistance. The molecules have been synthesised by conventional techniques and fully characterised by spectroscopic methods. The potency of these molecules was evaluated by in vitro enzyme specifc assays. Some of the molecules were active in micromolar concentrations and can easily be optimised to improve binding and activity. [ABSTRACT FROM AUTHOR]