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Background: To overcome drug resistance to current antimalarial drugs, we propose the synthesis and in vitro evaluation of the antiplasmodial activity of a series of 5-chlorobenzimidazolyl-chalcones against chloroquino sensitive (CQ-S) and chloroquino resistant (CQ-R) strains of P. falciparum. Objective: This study aimed to establish through structure-activity relationship studies and docking, the structural elements essential for antiplasmodial activities. Methods: The antiplasmodial activity of these benzimidazolylchalcones was carried out according to the Rieckmann microtest technique, followed by the determination of the concentrations inhibiting 50% of the production of parasitic HRP2 antigens (IC50) by ELISA. Chloroquine was used as a reference molecule with a sensitivity threshold set at 100 µM. Molecular docking was performed using sensitive (PDB ID: 1J3I) and resistant (PDB ID: 4DP3) dihydrofolate reductase-thymidylate synthase proteins (PfDHFR-TS). Results: All benzimidazolylchalcones tested expressed antiplasmodial activities especially against chloroquine resistant isolates (IC50 = 0.32-44.38 µM). The best profile against both isolates was the methoxylated derivative (3e) with an IC50 ranging from 0.32 to 1.96 µM. This compound had the best antimalarial activity against CQ-S isolates. On CQ-R isolates, the unsubstituted 5-chlorobenzimidazole derivative (3b) had exalted activity (IC50 = 0.78 µM). We selected a weakly active non-chlorinated derivative 3a and chlorinated derivatives 3b, 3d, 3e and 3f) with IC50< 3µM against the chloroquine-resistant strain to perform docking studies. These revealed that the pyrrolic nitrogen of benzimidazole and the ketone of propenone are the main chemical entities involved in the interaction at the receptor. Moreover, ADMET studies showed favorable pharmacokinetic properties. Conclusion: Molecular docking studies confirmed the experimental findings and revealed the possible interactions pattern. Derivatives 3b and 3e, which showed promising binding affinities against PfDHFR-TS, can be proposed as lead compounds for the development of antimalarial drug candidates.

Malaria continues to kill thousands of people worldwide. People South of the Sahara are paying the heaviest price for this epidemic. In addition, the resistance of Plasmodium falciparum which spreads to artemisinin derivatives becomes worrying. To respond to this emergency, the search for new molecules effective against the parasite is essential. Otherwise, chalcones have shown their potential as an effective pharmaceutical agent in numerous studies. However, despite their mainly antiparasitic efficacy, several compounds have been shown to be cytotoxic. This study aimed to assess the cytotoxic profile of chalcone derivatives. Cytotoxicity tests were carried out according to the method described by Taylor and collaborators on Vero cells. The 96-well plates were used in carrying out this study, 100 µl of the compounds were added with concentrations ranging from 7.5 to 1000 µg/ml in DMEM. The results obtained report three compounds derivatives (Chal_B14, Chal_B17 & Chal_SCA03) no-cytotoxic with LDH product values between 129 - 132.5 U/L and ATP ranging from 8.55 to 13.6 RLU. The IC50s for no-cytotoxic compounds ranged from 102 to 236 µM. On the other hand, the cytotoxic compounds had IC50s of less than 30 µM. The results of this study show that the derivatives Chal_B14, Chal_B17 & Chal_SCA03 are candidate compounds with a view to finding new molecules.

The synthesis of a hybrid mol­ecule is reported. The crystal structure of the monohydrate was investigated using Hirshfeld surface analysis and enrichment contact ratios. Hydrogen bonds induced by guest water mol­ecules are the main driving force in crystal packing formation., In the title hydrated hybrid compound C14H14N2OS2·H2O, the planar imidazo[1,2-a]pyridine ring system is linked to the 1,3-di­thiol­ane moiety by an enone bridge. The atoms of the C—C bond in the 1,3-di­thiol­ane 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 intra­molecular C—H⋯O hydrogen bond, which generates an S(6) graph-set motif. In the crystal, the hybrid mol­ecules are associated in R 2 2(14) dimeric units by weak C—H⋯O inter­actions. O—H⋯O hydrogen bonds link the water mol­ecules, forming infinite self-assembled chains along the b-axis direction to which the dimers are connected via O—H⋯N hydrogen bonding. Analysis of inter­molecular contacts using Hirshfeld surface analysis and contact enrichment ratio descriptors indicate that hydrogen bonds induced by water mol­ecules are the main driving force in the crystal packing formation.

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.

The management of candidiasis, once effective, is becoming more and more difficult with the increase of resistance of various Candida species to classical antifungals. It is in this context that we reported in our previous works the pharmacochemical development of new diazaheteroaryls derivatives functionalized with a Michael acceptor such as arylpropenone, arylacrylonitrile and arylcyanopropenone. These diazaheteroaryls derivatives with benzimidazolyl-arylpropenone or benzimidazolyl-arylacrylonitriles or benzimidazolyl-arylcyanopropenone and imidazopyridinyl-arylpropenones structure were obtained by chemical synthesis and then characterized by the usual spectroscopic methods (NMR and MS). The anticandidosic activities of these derivatives expressed as Minimum Inhibitory Quantity (MIQ) were determined in vitro on a clinical strain of Candida albicans, following the bioautography technique. The results show that diazaheteroaryls functionalized by a Michael acceptor have remarkable activities with IMQ ranging from 10 to 0.16 µg. Moreover, the anticandidosic performance of the different derivatives were related to the nature of the Michael acceptor and the structural variations undertaken on the benzene homocycle. This paper, which is the synthesis of a decade of research by our team, will address the pharmacochemical design, chemical synthesis and overall serial structure-anticandidosic activity studies of diaza-heteroaryls functionalized with a Michael acceptor in order to propose compounds that can be developed as anticandidosic drug candidates.

International audience; 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.

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.

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.

The aim of this study is to find potent biomolecules against infectious germs. Based on the reactivity of some key positions of the benzimidazole core, the first part of this work consisted of the synthesis of a series of substituted 2-thioalkylaryl-benzimidazoles 3a-d. Then, another series of N -alkyl-2-thioalkylarylbenzimidazoles 5a-d, 7a-c and 9b-c was also prepared from 2-thioalkylaryl-benzimidazoles by substitution on position-1 of benzimidazole core using the corresponding functionalized ethyl. The chemical structures of these compounds are determined by NMR ( 1 H, 13 C) and mass spectrometry. The second part concerned the in vitro antifungal activity evaluation of some of the synthesized compounds on Candida albicans . According to the results of evaluation, four compounds (3b, 3c, 3d and 9c) of the substituted 2-thioalkylaryl-benzimidazoles prove to be potent antifungal agent. Introduction of nitro group (NO 2 ) increased significantly the antifungal activity so that their IMQ is ranging between 0.03 and 0.008 μg (or 333 to 1250 times more efficient than the ketoconazole’s). Keywords : synthesis of 2-thioalkylaryl-benzimidazole, antifungal activity, candida albicans.

International audience; 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.

A series of 3-(3-Arylpropenoyl)imidazopyridine (5a to z) was synthesized by crotonization reaction of 2-methyl-3-acetylimidazopyridine with arylaldehyde derivatives. Structuraldetermination of these new chalcones was done by 1H nuclear magnetic resonance (NMR),13C NMR and electrospray ionization (ESI) mass spectroscopy. All compounds have beenevaluated in vitro for their anthelmintic activities against Haemonchus contortus. Compounds5n, 5s, 5t and 5w showed a great nematicidal activity (LC100) ranging between 0.0005 and0.002 µg/ml. The activity of these four chalcones was equivalent to that of fenbendazole andivermectin which were reference anthelmintic drugs. This study has shown that imidazopyridine-chalcone derivatives are promising candidates for the development of new anthelmintic agents. Key words: Haemonchus contortus, imidazopyridine, chalcone, nematicidal activity.

International audience; 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.

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.

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.

The title compound, C13H14N2OS2·H2O, appears in the form of bimolecular aggregate in which molecular 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 intramolecular 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 supramolecular structure consisting of perpendicular infinite molecular chains running along the a and c axes.