Discovery of imidazo[1,2-a]pyridine-based anthelmintic targeting cholinergic receptors of Haemonchus contortus.

We report the synthesis of a series of imidazo[1,2-a]pyridine-based molecules as anthelmintic against the livestock parasite Haemonchus contortus. The molecules were tested by using Larval Paralysis Test (LPT), in order to target ionic channels, as most of the prominent marketed anthelminthics present such mechanism of action. The most active compound (5e) displayed paralysis on H. contortus stage 3 larvae until 31.25 µM. Effect of 5e on H. contortus cholinergic receptors (L-AChR1 and 2) was characterized via electrophysiological measurement and a rare antagonist mode of action was unveiled.

[Direct current cardioversion in Abidjan: report of a ten-year practice in Institute of Cardiology of Abidjan, Ivory Coast]. / Choc électrique externe à Abidjan : bilan de dix ans de pratique à l'Institut de Cardiologie d'Abidjan, Côte d'Ivoire.

UNLABELLED: Direct current cardioversion is effective in arrhythmias' termination. Few is known about its use in our practice. This work aims to report its outcomes over a ten-year period in Abidjan. METHOD: One thousand, three hundred and ninety one charts of arrhythmic patients were reviewed. RESULTS: Cardioversion was attempted in 102 patients. One hundred and eighty one shocks were delivered with a mean energy of 262, 1 joules. Success occurred in 84 patients (82,3%). Cardioversion failed in 18 patients mostly in atrial fibrillation. Eight serious complications (7,8%) occurred including 1 sinus node dysfunction, 1 pulmonary oedema, 1 metrorrhagia, 2 stroke, 1 pulmonary embolism. Two patients with ventricular tachycardia died of end-stage heart failure and aftermath of a mitral valve surgery. CONCLUSION: Direct current cardioversion is effective and safe in our practice. Complications are predominantly due to the medical environment such as antiarrhythmic drugs use or clinical conditions.

[Not Available]. / Choc électrique externe à Abidjan : bilan de dix ans de pratique à l'Institut de Cardiologie d'Abidjan, Côte d'Ivoire.

UNLABELLED: Direct current cardioversion is effective in arrhythmias' termination. Few is known about its use in our practice. This work aims to report its outcomes over a ten-year period in Abidjan. METHOD: One thousand, three hundred and ninety one charts of arrhythmic patients were reviewed. RESULTS: Cardioversion was attempted in 102 patients. One hundred and eighty one shocks were delivered with a mean energy of 262, 1 joules. Success occurred in 84 patients (82,3%). Cardioversion failed in 18 patients mostly in atrial fibrillation. Eight serious complications (7,8%) occurred including 1 sinus node dysfunction, 1 pulmonary oedema, 1 metrorrhagia, 2 stroke, 1 pulmonary embolism. Two patients with ventricular tachycardia died of end-stage heart failure and aftermath of a mitral valve surgery. CONCLUSION: Direct current cardioversion is effective and safe in our practice. Complications are predominantly due to the medical environment such as antiarrhythmic drugs use or clinical conditions.

Exploration of potential prodrug approach of the bis-thiazolium salts T3 and T4 for orally delivered antimalarials.

We report here the synthesis and biological evaluation of a series of 37 compounds as precursors of potent antimalarial bis-thiazolium salts (T3 and T4). These prodrugs were either thioester, thiocarbonate or thiocarbamate type and were synthesized in one step by reaction of an alkaline solution of the parent drug with the appropriate activated acyl group. Structural variations affecting physicochemical properties were made in order to improve oral activity. Twenty-five of them exhibited potent antimalarial activity with IC(50) lower than 7nM against Plasmodium falciparum in vitro. Notably, 3 and 22 showed IC(50)=2.2 and 1.8nM, respectively. After oral administration 22 was the most potent compound clearing the parasitemia in Plasmodium vinckei infected mice with a dose of 1.3mg/kg.

Phenanthrolinic analogs of quinolones show antibacterial activity against M. tuberculosis.

Several phenanthrolinic analogs of quinolones have been synthesized and their antibacterial activity tested against Mycobacterium tuberculosis, other mycobacterial species and bacteria from other genera. Some of them show high activity (of the range observed for rifampicin) against M. tuberculosis replicating in vitro and in vivo (infected macrophages) conditions. These derivatives show the same activity with all or several M. tuberculosis complex bacterial mutants resistant to fluoroquinolones (FQ). This opens the way to the construction of new drugs for the treatment of FQ resistant bacterial infections, including tuberculosis. Several compounds showed also activity against Staphylococcus aureus and probably other species. These compounds do not show major toxicity. We conclude that the novel phenanthrolinic derivatives described here are potent hits for further developments of new antibiotics against bacterial infectious diseases including tuberculosis in particular those resistant to FQ.

Design and synthesis of amidoxime derivatives for orally potent C-alkylamidine-based antimalarial agents.

Within the frame of the design of prodrug candidates to deliver a C-alkylamidine antimalarial agent, we showed that specific O-substitutions were needed on the alkylamidoxime structure. Among the newly synthesized molecules, bis-oxadiazolone and bis-O-methylsulfonylamidoxime derivatives induced a complete clearance of parasitemia in mice after oral administration.

1-(2-Methyl-imidazo[1,2-a]pyridin-3-yl)-3,3-bis-(methyl-sulfan-yl)prop-2-enone monohydrate.

The title compound, C(13)H(14)N(2)OS(2)·H(2)O, appears in the form of bimolecular aggregate in which mol-ecular components are linked by O-H⋯N hydrogen bonding. The nine-membered imidazo[1,2-a]pyridine system is almost planar, with a mean deviation of 0.026 (1) Å. An intra-molecular C-H⋯O hydrogen bond forms within the imidazo[1,2-a]pyridine system. The crystal packing is consolidated by O-H⋯O and C-H⋯O hydrogen bonds, forming a supra-molecular structure consisting of perpendicular infinite mol-ecular chains running along the a and c axes.

Crystal structure, Hirshfeld surface analysis and contact enrichment ratios of 1-(2,7-di-methyl-imidazo[1,2-a]pyridin-3-yl)-2-(1,3-di-thio-lan-2-yl-idene)ethanone monohydrate.

In the title hydrated hybrid compound C14H14N2OS2·H2O, the planar imidazo[1,2-a]pyridine ring system is linked to the 1,3-di-thiol-ane moiety by an enone bridge. The atoms of the C-C bond in the 1,3-di-thiol-ane ring are disordered over two positions with occupancies of 0.579 (14) and 0.421 (14) and both disordered rings adopt a half-chair conformation. The oxygen atom of the enone bridge is involved in a weak intra-molecular C-H⋯O hydrogen bond, which generates an S(6) graph-set motif. In the crystal, the hybrid mol-ecules are associated in R 2 2(14) dimeric units by weak C-H⋯O inter-actions. O-H⋯O hydrogen bonds link the water mol-ecules, forming infinite self-assembled chains along the b-axis direction to which the dimers are connected via O-H⋯N hydrogen bonding. Analysis of inter-molecular contacts using Hirshfeld surface analysis and contact enrichment ratio descriptors indicate that hydrogen bonds induced by water mol-ecules are the main driving force in the crystal packing formation.

Ex vivo efficacy of selective chalcone derivatives on reference strains and field isolates of Plasmodium falciparum.

The extension of Plasmodium falciparum resistance to existing antimalarial drugs is worrying. Faced with this problem, the search for new and effective molecules is necessary. In this context, six chalcone derivatives (B1, B11, B14, B17, SCA02 and SCA03) were tested on field isolates and then reference strains to evaluate their antiplasmodial activity by using the Rieckmann semi-microtest, recommended by WHO, for in vitro and ex vivo activity tests. Compounds B14 and B17 exhibited promising antiplasmodial activities (IC50s: 14.41-16.40 µM) regardless of the type of isolate. Compounds B1, B11, SCA02 and SCA03 showed a moderate inhibition of field isolates (IC50S: 25.63-48.29 µM) and very good activity against reference strains (IC50s: 3.82-10.03 µM). Therefore, more structural modulations should improve their efficiency and make these molecules very good candidates for future effective antimalarial drugs.

Potent antimalarial activity of 2-aminopyridinium salts, amidines, and guanidines.

We describe the design, synthesis, and antimalarial activity of 60 bis-tertiary amine, bis-2(1 H)-imino-heterocycle, bis-amidine, and bis-guanidine series. Bis-tertiary amines with a linker from 12 to 16 methylene groups were active against the in vitro growth of Plasmodium falciparum within the 10 (-6)-10 (-7) M concentration range. IC 50 decreased by 2 orders of magnitude for bis-2-aminopyridinium salts, bis-amidines, and bis-guanidines (27 compounds with IC 50 < 10 nM). Increasing the alkyl chain length from 6 to 12 methylene groups led to increased activity, while beyond this antimalarial activity decreased. Antimalarial activities appear to be strictly related to the basicity of the cationic head with an optimal p K a over 12.5. Maximal activity occurs for bis-2-aminopyridinium, two C-duplicated bis-amidines, and three bis-guanidines, with IC 50 values lower than 1 nM. In comparison to similar quaternary ammonium salts, amidinium compounds have distinct structural requirements for antimalarial activity and likely additional binding opportunities on account of their hydrogen-bond-forming properties.

Disulfide prodrugs of albitiazolium (T3/SAR97276): synthesis and biological activities.

We report herein the design, synthesis, and biological screening of a series of 15 disulfide prodrugs as precursors of albitiazolium bromide (T3/SAR97276, compound 1), a choline analogue which is currently being evaluated in clinical trials (phase II) for severe malaria. The corresponding prodrugs are expected to revert back to the active bis-thiazolium salt through an enzymatic reduction of the disulfide bond. To enhance aqueous solubility of these prodrugs, an amino acid residue (valine or lysine) or a phosphate group was introduced on the thiazolium side chain. Most of the novel derivatives exhibited potent in vitro antimalarial activity against P. falciparum. After oral administration, the cyclic disulfide prodrug 8 showed the best improvement of oral efficacy in comparison to the parent drug.

Synthesis and antimalarial activity of new 1,12-bis(N,N'-acetamidinyl)dodecane derivatives.

Amidoxime and O-substituted derivatives of the bis-alkylamidine 1,12-bis(N,N'-acetamidinyl)dodecane were synthesized and evaluated as in vitro and in vivo antimalarial prodrugs. The bis-O-methylsulfonylamidoxime 8 and the bis-oxadiazolone 9 derivatives show relatively potent antimalarial activity after oral administration.