Novel flexible biphenyl DHFR inhibitors with improved antimalarial activity.

As pregnant women and young children remain the first victims of malaria worldwide, the search for new antimalarials has been focusing on compounds with a high safety profile and extended efficacy. In a previous study, a rigid biphenyl DHFR inhibitor was developed by fragment-based screening, displaying sub nM enzyme inhibition but poor antiparasitic activity, presumably due to its low flexibility. Here, we report a new series of compounds that combines the biphenyl fragment with a flexible linker.

Discovery of rigid biphenyl DHFR inhibitors using a fragment linking strategy.

dihydrofolate reductase (DHFR), a historical target for antimalarials, has been considered compromised due to resistance inducing mutations caused by pyrimethamine () overexposure. The clinical candidate has demonstrated that inhibitors could efficiently target both -sensitive and -resistant parasites through careful drug design. Yet, clinical development has been limited by its pharmacokinetic profile, incompatible with single dose regimen.

Key interactions of pyrimethamine derivatives specific to wild-type and mutant dihydrofolate reductase based on 3D-QSAR, MD simulations and quantum chemical calculations.

dihydrofolate reductase-thymidylate synthase (DHFR-TS) is an important target enzyme in malarial chemotherapy. An understanding of how novel inhibitors interact with wild-type (wtDHFR), quadruple-mutant (qmDHFR), and human (DHFR) enzymes is required for the development of these compounds as antimalarials. This study is focused on a series of -Cl and -Cl phenyl analogs of pyrimethamine with various flexible 6-substituents.

Discovery of new non-pyrimidine scaffolds as DHFR inhibitors by fragment-based screening.

In various malaria-endemic regions, the appearance of resistance has precluded the use of pyrimidine-based antifolate drugs. Here, a three-step fragment screening was used to identify new non-pyrimidine dihydrofolate reductase (DHFR) inhibitors. Starting from a 1163-fragment commercial library, a two-step differential scanning fluorimetry screen identified 75 primary fragment hits.

Flexible diaminodihydrotriazine inhibitors of Plasmodium falciparum dihydrofolate reductase: Binding strengths, modes of binding and their antimalarial activities.

A series of flexible diaminodihydrotriazines or cycloguanil (Cyc) analogues are developed and shown to inhibit P. falciparum dihydrofolate reductase (PfDHFR) of the wild type or those carrying either single (S108N), double (C59R + S108N and A16V + S108T), triple (N51I + C59R + S108N and C59R + S108N + I164L) or quadruple (N51I + C59R + S108N + I164L) mutations, responsible for antifolate resistance. The flexibility of the side chain at position N has been included in the design so as to avoid unfavourable steric interaction with the side chain of residue 108 of the resistant mutants.

6-Hydrophobic aromatic substituent pyrimethamine analogues as potential antimalarials for pyrimethamine-resistant Plasmodium falciparum.

The series of des-Cl (unsubstituted) and m-Cl phenyl analogues of PYR with various flexible 6-substituents were synthesized and studied for the binding affinities with highly resistant quadruple mutant (QM) DHFR. The derivatives carrying 4 atoms linker with a terminal carboxyl substituted on the aromatic ring exhibited good inhibition to the QM enzyme and also showed effective antimalarial activities against resistant P. falciparum bearing the mutant enzymes with relatively low cytotoxicity to mammalian cells.

Validation of deoxyhypusine synthase as an antimalarial target.

Background: Hypusination is an essential post-translational modification in eukaryotes. The two enzymes required for this modification, namely deoxyhypusine synthase (DHS) and deoxyhypusine hydrolase are also conserved. human malaria parasites possess genes for both hypusination enzymes, which are hypothesized to be targets of antimalarial drugs.