Development of benzophenone-based farnesyltransferase inhibitors as novel antimalarials.

The development of farnesyltransferase inhibitors directed against Plasmodium falciparum is a strategy towards new drugs against malaria. Previously, we described benzophenone-based farnesyltransferase inhibitors with high in vitro antimalarial activity but no in vivo activity. Through the introduction of a methylpiperazinyl moiety, farnesyltransferase inhibitors with in vivo antimalarial activity were obtained.

Non-thiol farnesyltransferase inhibitors: N-(4-acylamino-3-benzoylphenyl)-3-[5-(4-nitrophenyl)-2-furyl]acrylic acid amides.

We have designed the nitrophenylfurylacryl-substituted benzophenone 4f as a non-thiol farnesyltransferase inhibitor utilizing a novel aryl binding site of farnesyltransferase. Variation of the 2-acylamino substituent at the benzophenone core structure of our initial lead 4f yielded several non-thiol farnesyltransferase inhibitors with improved activity. These compounds display activity in the low nanomolar range.

Structure-activity relationships of novel anti-malarial agents. Part 6: N-(4-arylpropionylamino-3-benzoylphenyl)-[5-(4-nitrophenyl)-2-furyl]acrylic acid amides.

We have demonstrated that the p-trifluoromethylphenylpropionylamino residue at the 2-position of the core structure leads to an active benzophenone-type anti-malarial agent. The attempt to improve water solubility by introduction of an amino group into the alpha-position of the arylpropionyl residue resulted in decreased activity.

Structure-activity relationships of novel anti-malarial agents: part 5. N-(4-acylamino-3-benzoylphenyl)-[5-(4-nitrophenyl)-2-furyl]acrylic acid amides.

We have developed the [5-(4-nitrophenyl)-2-furyl]acrylic acid substituted benzophenone 4g as a novel lead for anti-malarial agents. Here, we demonstrated that the acyl residue at the 2-amino group of the benzophenone core structure has to be a phenylacetic acid substructure substituted in its para-position with methyl or other substituents of similar size. The trifluoromethyl substituted derivative displayed an IC(50) of 47 nM against the multi-drug resistant Plasmodium falciparum strain Dd2.

Non-thiol farnesyltransferase inhibitors: evaluation of different AA(X)-peptidomimetic substructures in combination with arylic cysteine replacements.

In the course of our studies on non-thiol farnesyltransferase inhibitors based on the 2, 5-diaminobenzophenone AAX-peptidomimetic substructure, we have developed the (4-nitrophenyl)butyryl (R(1)), the (2-naphthyl)acryloyl (R(2)), the 4-nitrocinnamoyl (R(3)), and the 5-(4-nitrophenyl)furylacryloyl (R(4)) groups as useful cysteine replacements. In this study, we combined these four groups with other AA(X)-peptidomimetic substructures (5-10: R = H) reported in the literature. The 5-(4-nitrophenyl)furylacryloyl moiety (R(4)) turned out to be the most useful non-thiol cysteine replacement yielding in all cases the most active inhibitors.

Non-thiol farnesyltransferase inhibitors: N-(4-Acylamino-3-benzoylphenyl)-4-nitrocinnamic acid amides.

We have developed the 4-nitrocinnamoyl substituted benzophenone 4a as a novel non-thiol farnesyltransferase inhibitor. Replacement of the p-tolyl moiety of our initial lead structure 4a by different para and ortho substituted phenyl residues as well as by 1-naphthyl resulted in derivatives with considerably enhanced activity displaying IC(50) values between 42 and 52 nM. These compounds represent novel, readily accessible non-thiol farnesyltransferase inhibitors being more active than the corresponding thiol-containing analogues.