Synthesis and in vitro and in vivo antimalarial activity of N1-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine derivatives.

Three series of monoquinolines consisting of a 1,4-bis(3-aminopropyl)piperazine linker and a large variety of terminal groups were synthesized. Our aim was to prove that in related bisquinoline, it is the second quinoline moiety that is responsible for cytotoxicity and that it is not an absolute requirement for overcoming resistance to chloroquine (CQ). Eleven compounds displayed a higher selectivity index (ratio CC50/IC50 activity) than CQ, and one of them cured mice infected by Plasmodium berghei.

Synthesis and biological evaluation of benzimidazole derivatives as potent AMP-activated protein kinase activators.

Design, synthesis and structure-activity relationships of benzimidazole derivatives as activators of the AMP-activated protein kinase (AMPK) are presented in this paper. AMPK is the central component of a protein kinase cascade that plays a key role in the regulation of energy balance. Once activated, AMPK initiates a series of responses that are aimed at restoring the energy balance of the cell and recent studies have indicated that AMPK plays an important role in regulation of the whole-body energy metabolism. The following study based on the lead compound S27847 involved modification of three regions of this compound. Preliminary structure-activity relationships are being described.

Synthesis and antimalarial evaluation of new N1-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine derivatives.

Synthesis and evaluation of the activity of new N(1)-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine derivatives against a chloroquine-resistant strain of Plasmodium falciparum are described. Selectivity indices were improved for two compounds versus the lead 1, the bis-cyclopropylmethyl derivative, thus increasing the therapeutic interest of our family. As our previous studies conducted on the mode of action of our compounds made us hypothesize the existence of original mechanisms and/or original targets, terminal amino derivatives can be considered as promising tools further mechanistical studies, as probes for affinity chromatography.

Synthesis and pharmacological evaluation of Tic-hydantoin derivatives as selective sigma1 ligands. Part 2.

Herein is described a new class of selective sigma1 ligands consisting of tetrahydroisoquinoline-hydantoin (Tic-hydantoin) derivatives. Compound 1a has high affinity (IC50 = 16 nM) for sigma1 receptor and is selective in a large panel of therapeutic targets. This study presents structural changes on the side chain of the Tic-hydantoin core. Analogs of higher affinity could be identified (IC50 approximately 2-3 nM).

Synthesis and pharmacological evaluation of Tic-hydantoin derivatives as selective sigma1 ligands. Part 1.

Herein is described a new class of selective sigma1 ligands consisting of tetrahydroisoquinoline-hydantoin (Tic-hydantoin) derivatives. Compound 3a has high affinity (IC50 = 16 nM) for the sigma1 receptor and is selective in a large panel of therapeutic targets. This first study presents structural changes around the Tic-hydantoin core, leading to a Tic-hydantoin analogue with a higher sigma1 affinity (IC50 approximately 1 nM).

Synthesis and antimalarial evaluation of new 1,4-bis(3-aminopropyl)piperazine derivatives.

Synthesis and evaluation of the activity of a new family of 1,4-bis(3-aminopropyl)piperazine derivatives against a chloroquine-resistant strain of Plasmodium falciparum, and as inhibitors of beta-hematin formation, are described. The highest antimalarial activities were obtained for compounds displaying the highest predicted vacuolar accumulation ratios and the best potencies as inhibitors of beta-hematin formation. The most potent compound displayed an activity 3-fold better than chloroquine for a comparable selectivity index upon MRC-5 cells. Therefore, in this series, the replacement of the 7-chloroquinoline group can constitute a strong rationale for further investigation.

Comparison of the inhibition of human and Trypanosoma cruzi prolyl endopeptidases.

Prolyl endopeptidases (PEPs) have been found in numerous species. Inhibitors of human enzyme could correct cognitive deficits in Alzheimer patients while inhibition of Trypanosoma cruzi PEP could prevent invasion phase in Chagas disease. A structure-activity relationship study carried out in a tetrahydroisoquinoline series allowed to obtain potent competitive inhibitors superior to SUAM-1221. Besides, inhibitors expected to act according to an irreversible mechanism revealed to be superior to JPT-4819, for applications linked to human enzyme inhibition.