New synthesis of tic-hydantoins sigma-1 ligands and pharmacological evaluation on cocaine-induced stimulant effects.

Activation of the newly identified σ1 chaperone protein is involved in several aspects of the psychostimulant and addictive effects of cocaine. The development of ligands that selectively target the σ1 protein may lead to putative potent anti-cocaine agents. We report here a new and more convergent synthetic pathway to amino side chain substituted hydantoins. Twenty new analogs of our lead compound were synthesized. None of them showed better in vitro affinity for σ1 receptor than our lead compound. Nevertheless, three of them, obtained as racemates, showed high in vitro affinity and selectivity for σ1 receptor. A preliminary in vivo evaluation of their pharmacological activity identified compound 22 as one that increases cocaine-induced locomotor stimulation and therefore acts as a potential efficient σ1 agonist.

Parallel synthesis and anti-malarial activity of a sulfonamide library.

Solution-phase synthesis and evaluation of a library of 31 sulfonamides as inhibitors of a chloroquine-resistant strain of Plasmodium falciparum are described. The most potent compound displayed an activity 100-fold better than chloroquine. Experiments using a fluorescent sulfonamide derivative suggest that their site of action inside the parasite is different to that of chloroquine.

Synthesis and in vitro and in vivo antimalarial activity of new 4-anilinoquinolines.

A new series of 4-anilinoquinolines with two proton-accepting side chains has been synthesized. Antimalarial activity and levels of cytotoxicity upon both MRC-5 cells and macrophages were found to be highly dependent upon the features of these side chains. Several compounds were found to be active in the low nanomolar range, against both chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro. From among them, a morpholino derivative cured mice infected by Plasmodium berghei and displayed a lower toxicity than amodiaquine upon mouse macrophages.

Antimalarial in-vivo activity of bis(9-amino-6-chloro-2-methoxyacridines).

In the fight against malaria, chemotherapy using bisacridines may represent an alternative method to overcoming chloroquine-resistance. Eight bis(9-amino-6-chloro-2-methoxyacridines), in which acridine moieties were linked by polyamines substituted with a side chain, were tested for their in-vivo activity upon mice infected by Plasmodium berghei. Three of the compounds revealed antimalarial activity but no relationship could be deduced from a comparison of in-vitro and in-vivo activities. N-alkylation of the central amino group generated toxicity and, therefore, only compounds N-acylated in this position can be selected as leads.