Non-thiol farnesyltransferase inhibitors: utilization of the far aryl binding site by arylthienylacryloylaminobenzophenones.

We recently described two novel aryl binding sites of farnesyltransferase. The 4- and 5-arylsubstituted thienylacryloyl moieties turned out as appropriate substituents for our benzophenone-based AAX-peptidomimetic capable for occupying the far aryl binding site.

Non-thiol farnesyltransferase inhibitors: N-(4-tolylacetylamino-3-benzoylphenyl)-3-arylfurylacrylic acid amides.

We have designed arylfurylacryl-substituted benzophenones as non-thiol farnesyltransferase inhibitors utilizing a novel aryl binding site of farnesyltransferase. These compounds display activity in the low nanomolar range.

Non-thiol farnesyltransferase inhibitors: utilization of the far aryl binding site by 5-cinnamoylaminobenzophenones.

We recently described two novel aryl binding sites of farnesyltransferase. In this study, the cinnamoyl residue was designed as an appropriate substituent for our benzophenone-based AAX-peptidomimetic compound capable of occupying the far aryl binding site.

Non-thiol farnesyltransferase inhibitors: utilization of the near aryl binding site by 5-arylacetylaminobenzophenones.

We recently described two novel aryl binding sites of farnesyltransferase. The arylacetyl residue was designed as an appropriate substituent for our benzo-phenone-based AAX-peptidomimetic compound capable of occupying the near aryl binding site which is located next to the catalytic zinc ion. Non-thiol farnesyl-transferase inhibitors with micromolar to submicromolar activity were obtained.

Non-thiol farnesyltransferase inhibitors: FTase-inhibition and cellular activity of benzophenone-based bisubstrate analogue farnesyltransferase inhibitors.

Some 5-acylaminoacylamino-benzophenone derivatives were designed as bisubstrate analogue farnesyltransferase inhibitors. These compounds turned out to be only weakly active against farnesyltransferase, but displayed an antiproliferative effect rendering them suitable for further development as a novel type of cytostatic agents.

Structure-activity relationships of novel anti-malarial agents. Part 7: N-(3-benzoyl-4-tolylacetylaminophenyl)-3-(5-aryl-2-furyl)acrylic acid amides with polar moieties.

In a previous report, we have provided evidence that novel anti-malarial compounds based on 2,5-diaminobenzophenone farnesyltransferase inhibitors might benefit from the presence of a polar moiety at the para position of the terminal phenyl of the arylfurylacryloyl partial structure. Here, we demonstrate that different moieties with hydrogen bond acceptor properties lead to equipotent or even improved anti-malarial activity in comparison to the nitro group described before.

Structure-activity relationships of novel anti-malarial agents. Part 4: N-(3-benzoyl-4-tolylacetylaminophenyl)-3-(5-aryl-2-furyl)acrylic acid amides.

In a previous report, we have described novel anti-malarial compounds based on a 2,5-diaminobenzophenone scaffold. Here, we have invesigated acryloyl derivatives carrying a biaryl structure consisting of a terminal aryl residue and a central 2-furyl ring. Several compounds were obtained in the series of para-substituted phenylfurylacryloyl derivatives that displayed improved anti-malarial activity in comparison to earlier described derivatives. From the structure-activity relationships it can be deduced that there has to be a lipophilic moiety in the para-position of the terminal phenyl residue. Furthermore, there are indications that, alternatively, activity may benefit from the presence of a polar moiety with hydrogen bond acceptor properties.

Non-thiol farnesyltransferase inhibitors: utilization of an aryl binding site by 5-arylacryloylaminobenzophenones.

We recently described a novel aryl binding site of farnesyltransferase. The 2-naphthylacryloyl residue was developed as an appropriate substituent for our benzophenone-based AAX-peptidomimetic capable of occupying this binding site, resulting in a non-thiol farnesyltransferase inhibitor with nanomolar activity. The activity of this inhibitor is readily explained on the basis of docking studies which show the 2-naphthyl residue fitting into the aryl binding site.