Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical Properties.

With the aim of increasing the structural diversity on the early antimalarial drug plasmodione, an efficient and versatile procedure to prepare a series of biaryl- and N-arylalkylamines as plasmodione analogues is described. Using the naturally occurring and commercially available menadione as starting material, a 2-step sequence using a Kochi-Anderson reaction and subsequent Pd-catalyzed Suzuki-Miyaura coupling was developed to prepare three representative biphenyl derivatives in good yields for antimalarial evaluation. In addition, synthetic methodologies to afford 3-benzylmenadione derivatives bearing a terminal -N(Me)2 or -N(Et)2 in different positions (ortho, meta and para) on the aryl ring of the benzylic chain of plasmodione were investigated through reductive amination was used as the optimal route to prepare these protonable N-arylalkylamine privileged scaffolds. The antimalarial activities were evaluated and discussed in light of their physicochemical properties. Among the newly synthesized compounds, the para-position of the substituent remains the most favourable position on the benzyl chain and the carbamate -NHBoc was found active both in vitro (42 nM versus 29 nM for plasmodione) and in vivo in Plasmodium berghei-infected mice. The measured acido-basic features of these new molecules support the cytosol-food vacuole shuttling properties of non-protonable plasmodione derivatives essential for redox-cycling. These findings may be useful in antimalarial drug optimization.

3-Substituted 2-isocyanopyridines as versatile convertible isocyanides for peptidomimetic design.

We report the use of 3-substituted 2-isocyanopyridines as convertible isocyanides in Ugi four-component reactions. The N-(3-substituted pyridin-2-yl)amide Ugi products can be cleaved by amines, alcohols, and water with Zn(OAc)2 as a catalyst. In addition, the applicability of the method was demonstrated in constrained di-/tripeptides bearing acid and base sensitive protective groups obtained via Ugi-4CR post-condensation modifications.

Efficient One-Pot Access to Trisubstituted 2-Benzazepin-3-ones as Constrained Pseudopeptide Analogues and Privileged Scaffolds.

BACKGROUND: Benzazepines received great attention in the field of medicinal chemistry since this scaffold has been recognized to belong to the important family of privileged templates. More specifically, the 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) is used as a core structure in a variety of constrained therapeutic peptide (turn) mimetics.Most of the synthetic approaches towards this template have focused on cyclizations which form the central 7-membered azepine ring. OBJECTIVE: Previous investigations in our group allowed an expansion of the substitution patterns in the 4-amino-benzazepin-3-one scaffold by introduction of methyl substituents at positions 4 and 5 of the azepinone ring system, but also to 1-aryl substituted compounds. These were the only trisubstituted analogues obtained to date. To introduce an additional point of diversification and conformational constraint useful for peptide mimicry, one can use bifunctional substrates in the Ugi reaction as reported in the present manuscript. METHOD: The 1-carboxamido-substituted Aba scaffold has been synthesized via the Ugi-3CR reaction starting from N-Phth-protected 2-formyl-L-Phe-OH with a set of amine and isocyanide derivatives. The most suited reaction conditions were applied, involving preformation of the imine in MeOH (0.1 M) in the presence of anhydrous Na2SO4 during 2 hours at room temperature, followed by the addition of an equimolar quantity of isocyanide prior to heating the reaction mixture at 80 °C for 20 hours, using sealed vial reaction conditions. RESULTS: The substituted Aba scaffolds were isolated in moderate yields (and diastereomeric ratio). This is due to the requirement for a double N-phthaloyl protection of the bifunctional building block, which prevents the use of an excess of amine reagent to drive the reaction conversion to completion, and some starting substrate always remains. Despite the moderate yields, the methodology is efficient since it only requires a limited number of synthetic steps in a final one-pot reaction. In most cases, the diastereomers could be separated by preparative RP-HPLC or via silica gel column chromatography. This is interesting from a medicinal chemistry point of view, since access is provided to the individual diastereomers. CONCLUSION: We have developed an efficient and useful one-pot strategy to access 1-substituted 4- aminobenzazepinone (Aba) derivatives via the Ugi-3CR reaction. To the best of our knowledge, these scaffolds are only accessible through the presented methodology. The obtained structural complexity, as well as the substitution versatility of these trisubstituted scaffolds, will allow their use in various biological applications.

A Redox-Active Fluorescent pH Indicator for Detecting Plasmodium falciparum Strains with Reduced Responsiveness to Quinoline Antimalarial Drugs.

Mutational changes in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) have been associated with differential responses to a wide spectrum of biologically active compounds including current and former quinoline and quinoline-like antimalarial drugs. PfCRT confers altered drug responsiveness by acting as a transport system, expelling drugs from the parasite's digestive vacuole where these drugs exert, at least part of, their antiplasmodial activity. To preserve the efficacy of these invaluable drugs, novel functional tools are required for epidemiological surveys of parasite strains carrying mutant PfCRT variants and for drug development programs aimed at inhibiting or circumventing the action of PfCRT. Here we report the synthesis and characterization of a pH-sensitive fluorescent chloroquine analogue consisting of 7-chloro-N-{2-[(propan-2-yl)amino]ethyl}quinolin-4-amine functionalized with the fluorochrome 7-nitrobenzofurazan (NBD) (henceforth termed Fluo-CQ). In the parasite, Fluo-CQ accumulates in the digestive vacuole, giving rise to a strong fluorescence signal but only in parasites carrying the wild type PfCRT. In parasites carrying the mutant PfCRT, Fluo-CQ does not accumulate. The differential handling of the fluorescent probe, combined with live cell imaging, provides a diagnostic tool for quick detection of those P. falciparum strains that carry a PfCRT variant associated with altered responsiveness to quinoline and quinoline-like antimalarial drugs. In contrast to the accumulation studies, chloroquine (CQ)-resistant parasites were observed cross-resistant to Fluo-CQ when the chemical probe was tested in various CQ-sensitive and -resistant parasite strains. NBD derivatives were found to act as redox cyclers of two essential targets, using a coupled assay based on methemoglobin and the NADPH-dependent glutathione reductase (GRs) from P. falciparum. This redox activity is proposed to contribute to the dual action of Fluo-CQ on redox equilibrium and methemoglobin reduction via PfCRT-mediated drug efflux in the cytosol and then continuous redox-dependent shuttling between food vacuole and cytosol. Taking into account these physicochemical characteristics, a model was proposed to explain Fluo-CQ antimalarial effects involving the contribution of PfCRT-mediated transport, methemoglobin reduction, hematin binding, and NBD reduction activity catalyzed by PfGR in CQ-resistant versus CQ-sensitive parasites. Therefore, introduction of NBD fluorophore in drugs is not inert and should be taken into account in drug transport and imaging studies.

T3P-Promoted, Mild, One-Pot Syntheses of Constrained Polycyclic Lactam Dipeptide Analogues via Stereoselective Pictet-Spengler and Meyers Lactamization Reactions.

A new convenient, mild, one-pot procedure is described for the diastereoselective synthesis of constrained 7,5- and 7,6-fused azabicycloalkanes. Using 2-formyl-L-tryptophan and 2-formyl-l-phenylalanine as bielectrophilic building blocks, T3P-mediated Pictet-Spengler and Meyers lactamization reactions were developed to present chiral and polycyclic aminoindolo- and aminobenzazepinone compounds in excellent yields. The conformationally constrained compounds can serve as templates for peptidomimetic research or polyheterocyclic privileged scaffolds.

One-pot isomerization-cross metathesis-reduction (ICMR) synthesis of lipophilic tetrapeptides.

An efficient, versatile and rapid method toward homologue series of lipophilic tetrapeptide derivatives (herein, the opioid peptides H-TIPP-OH and H-DIPP-OH) is reported. High atom economy and a minimal number of synthetic steps resulted from a one-pot tandem isomerization-cross metathesis-reduction sequence (ICMR), applicable both in solution and solid phase methodology. The broadly applicable synthesis proceeds with short reaction times and simple work-up, as illustrated in this work for alkylated opioid tetrapeptides.

Highly diastereoselective synthesis of 1-carbamoyl-4-aminoindoloazepinone derivatives via the Ugi reaction.

A one-pot procedure for the highly diastereoselective synthesis of 1-carbamoyl-4-amino-1,2,4,5-tetrahydroindolo[2,3-c]azepin-3-one derivatives is described. Using 2-formyl-L-tryptophan as a bifunctional building block, a catalyst-free Ugi-three-component reaction (Ugi-3CR) was developed to present trisubstituted indoloazepinones in good yields and excellent diastereomeric excess.