Achiel Haemers

Mycobacteria and the new quinolones.

Revue sur la plupart des etudes, in vitro et in vivo publiees sur les activites antibacteriennes de nouveaux quinolones

In vitro antioxidant profile of phenolic acid derivatives

Several caffeic acid esters isolated from propolis exhibit interesting antioxidant properties, but their in vivo use is compromised by hydrolysis of the ester bond in the gastrointestinal tract. Therefore, a series of caffeic acid amides were synthesized and their in vitro antioxidant profile was determined. A series of hydroxybenzoic acids, hydroxycinnamic acids, and the synthesized caffeic acid amides were tested for both their 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging and microsomal lipid peroxidation-inhibiting activity. Some of the highly active antioxidants were further tested by means of electron paramagnetic resonance for their hydroxyl radical scavenging activity. Since a promising antioxidant compound should show a lipid peroxidation-inhibiting activity at micromolar level and a low cytotoxicity, the cytotoxicity of the phenolic compounds was also studied. In all the assays used, the caffeic acid anilides and the caffeic acid dopamine amide showed an interesting antioxidant activity.

Synthesis and evaluation of caffeic acid amides as antioxidants

A series of amides of caffeic acid has been synthesised and their antioxidant properties evaluated as lipid peroxidation inhibitors. Anilides of caffeic acid were found to be very efficient antioxidants with IC50s of 0.3 microM.

Dipeptidyl peptidase IV inhibitors as new therapeutic agents for the treatment of Type 2 diabetes

Type 2 diabetes is the most prevalent form of diabetes. Incretin hormones play an important role in normal and pathological blood glucose homeostasis. The role of dipeptidyl peptidase IV (DPP IV) in the inactivation of glucagon-like peptide-1 (GLP-1), one of the most important incretins, is wellestablished. Therefore, DPP IV inhibitors are investigated as new therapeutic agents for the treatment of Type 2 diabetes. A summary of DPP IV inhibitors reported until 1998 and a more extensive discussion of more recent inhibitors found in literature and patent applications will be provided. The therapeutic potential of several aminoacyl pyrrolidides, aminoacyl thiazolidides and aminoacyl pyrrolidine-2-nitriles will be reviewed.

Prolyl Peptidases Related to Dipeptidyl Peptidase IV: Potential of Specific Inhibitors in Drug Discovery.

Dipeptidyl peptidase IV (DPP IV) is a validated target for the treatment of type 2 diabetes, with several inhibitors currently in phase 3 clinical trials. This review will mainly focus on proline-specific dipeptidyl peptidases related to DPP IV: fibroblast activation protein (FAP), dipeptidyl peptidase 8 (DPP8), dipeptidyl peptidase 9 (DPP9) and dipeptidyl peptidase II (DPP II). The biochemical and biological properties of these enzymes will be discussed, as well as the therapeutic potential of their inhibition. The development of potent and selective inhibitors for each of these peptidases will be described.

Synthesis and antiplasmodial activity of aminoalkylamino-substituted neocryptolepine derivatives.

A series of chloro- and aminoalkylamino-substituted neocryptolepine (5-methyl-5H-indolo[2,3-b]quinoline) derivatives were synthesized and evaluated as antiplasmodial agents. The evaluation also included cytotoxicity (MRC5 cells), inhibition of beta-hematin formation, and DNA interactions (DNA-methyl green assay). Introduction of aminoalkylamino chains increased the antiplasmodial activity of the neocryptolepine core substantially. The most efficient compounds showed antiplasmodial activities in the nanomolar range. N(1),N(1)-Diethyl-N(4)-(5-methyl-5H-indolo[2,3-b]quinolin-8-yl)pentane-1,4-diamine 11c showed an IC(50) of 0.01 microM and a selectivity index of 1800.

Suzuki reactions on chloropyridazinones: an easy approach towards arylated 3(2H)-pyridazinones

Abstract The synthesis of 4-aryl-5-methoxy-, 5-aryl-4-methoxy- and 4,5-diaryl-3(2H)-pyridazinones via Suzuki palladium-catalysed cross-coupling reactions with the corresponding chloro-3(2H)-pyridazinones is described.

Structure–Activity Relationship Studies on Isoindoline Inhibitors of Dipeptidyl Peptidases 8 and 9 (DPP8, DPP9): Is DPP8-Selectivity an Attainable Goal?

This work represents the first directed study to identify modification points in the topology of a representative DPP8/9-inhibitor, capable of rendering selectivity for DPP8 over DPP9. The availability of a DPP8-selective compound would be highly instrumental for studying and untwining the biological roles of DPP8 and DPP9 and for the disambiguation of biological effects of nonselective DPP-inhibitors that have mainly been ascribed to blocking of DPPIVs action. The cell-permeable DPP8/9-inhibitor 7 was selected as a lead and dissected into several substructures that were modified separately for evaluating their potential to contribute to selectivity. The obtained results, together with earlier work from our group, clearly narrow down the most probable DPP8-selectivity imparting modification points in DPP8/9 inhibitors to parts of space that are topologically equivalent to the piperazine ring system in 7. This information can be considered of high value for future design of compounds with maximal DPP8 selectivity.

A new approach towards the synthesis of 3-amino-6-(hetero)arylpyridazines based on palladium catalyzed cross-coupling reactions

The synthesis of 3-amino-6-(hetero)arylpyridazines via palladium catalyzed cross-coupling reactions (Suzuki, Stille) on 3-amino-6-chloropyridazine (1a) and 3-amino-6-iodopyridazine (1b) has been investigated. Comparison of the results shows that there is no need to start from 1b. An improved method for the synthesis of compound 1b from 1a is also described.

Influence of N substitution on antimycobacterial activity of ciprofloxacin.

Ciprofloxacin analogs with various substitutions on the piperazine nitrogen were tested against several mycobacteria. In contrast to what has been found with other gram-positive and gram-negative bacteria, alkyl analogs such as N-isopropylciprofloxacin were shown to be significantly more active than ciprofloxacin. MICs of 0.125 microgram/ml against Mycobacterium tuberculosis were found.