Lariat Ethers with Pendant Phenanthridine Units. Synthesis and Complexation of Na- and K-Picrate.

Lariat ethers 12 and 13 with appended phenanthridine fluorophoric units have been prepared as potential fluorescent chemosensor molecules for alkaline metal salts possessing aromatic anions. The starting 8-ethyloxycarbonylamino-6-methylphenanthridine (1) was converted via 2, 3, 6 and 7 to N-(2-tosylethyl)-derivatives 4 and 8 suitable for N-alkylations of diaza- and aza-18-crown-6. However, the alkylations failed, giving the 2-oxazolidinone derivative 5 formed by intramolecular cyclization of phenanthridine N-carbamate derivatives 4 and 8 in basic conditions. The phenanthridine derivative 10 having benzyl instead carbamate protection on 8-amino group successfully alkylated mono- and diaza-crown ethers, giving lariats 12 and 14. Subsequent removal of benzyl protection groups in acidic conditions gave lariats 13 and 15. Lariat 12 was found to form unique Na- and K-picrate complexes with the metal cation bound in the crown cavity and picrate anion intercalated between phenanthridine units

New Bicyclic Azalide Macrolides Obtained by Tandem Palladium Catalyzed Allylic Alkylation/Conjugated Addition Reaction

Unprecedented tandem allylic alkylation/intermolecular Michael addition was used in the preparation of novel bicyclic azalides. NMR spectroscopy was used not only to unambiguously determine and characterize the structures of these unexpected products of chemical reaction but also to investigate the effect the rigid bicyclic modification has on the conformation of the whole molecule. Thus, some of the macrolides prepared showed antibacterial activity in the range of well-known antibiotic drug azithromycin

Structure and conformational analysis of spiroketals from 6-O-methyl-9(E)-hydroxyiminoerythronolide A

Three novel spiroketals were prepared by a one-pot transformation of 6-O-methyl-9(E)-hydroxyiminoerythronolide A. We present the formation of a [4.5]spiroketal moiety within the macrolide lactone ring, but also the unexpected formation of a 10-C=11-C double bond and spontaneous change of stereochemistry at position 8-C. As a result, a thermodynamically stable structure was obtained. The structures of two new diastereomeric, unsaturated spiroketals, their configurations and conformations, were determined by means of NMR spectroscopy and molecular modelling. The reaction kinetics and mechanistic aspects of this transformation are discussed. These rearrangements provide a facile synthesis of novel macrolide scaffolds

Antimalarial activity of 9a-N substituted 15-membered azalides with improved in vitro and in vivo activity over azithromycin

Novel classes of antimalarial drugs are needed due to emerging drug resistance. Azithromycin, the first macrolide investigated for malaria treatment and prophylaxis, failed as a single agent and thus novel analogues were envisaged as the next generation with improved activity. We synthesized 42 new 9a-N substituted 15-membered azalides with amide and amine functionalities via simple and inexpensive chemical procedures using easily available building blocks. These compounds exhibited marked advances over azithromycin in vitro in terms of potency against Plasmodium falciparum (over 100-fold) and high selectivity for the parasite and were characterized by moderate oral bioavailability in vivo. Two amines and one amide derivative showed improved in vivo potency in comparison to azithromycin when tested in a mouse efficacy model. Results obtained for compound 6u, including improved in vitro potency, good pharmacokinetic parameters, and in vivo efficacy higher than azithromycin and comparable to chloroquine, warrant its further development for malaria treatment and prophylaxis

A novel class of fast‐acting antimalarial agents: Substituted 15‐membered azalides

Background and purpose: Efficacy of current antimalarial treatments is declining as a result of increasing antimalarial drug resistance, so new and potent antimalarial drugs are urgently needed. Azithromycin, an azalide antibiotic, was found useful in malaria therapy, but its efficacy in humans is low. ----- Experimental approach: Four compounds belonging to structurally different azalide classes were tested and their activities compared to azithromycin and chloroquine. in vitro evaluation included testing against sensitive and resistant Plasmodium falciparum, cytotoxicity against HepG2 cells, accumulation and retention in human erythrocytes, antibacterial activity, and mode of action studies (delayed death phenotype and haem polymerization). in vivo assessment enabled determination of pharmacokinetic profiles in mice, rats, dogs, and monkeys and in vivo efficacy in a humanized mouse model. ----- Key results: Novel fast-acting azalides were highly active in vitro against P. falciparum strains exhibiting various resistance patterns, including chloroquine-resistant strains. Excellent antimalarial activity was confirmed in a P. falciparum murine model by strong inhibition of haemozoin-containing trophozoites and quick clearance of parasites from the blood. Pharmacokinetic analysis revealed that compounds are metabolically stable and have moderate oral bioavailability, long half-lives, low clearance, and substantial exposures, with blood cells as the preferred compartment, especially infected erythrocytes. Fast anti-plasmodial action is achieved by the high accumulation into infected erythrocytes and interference with parasite haem polymerization, a mode of action different from slow-acting azithromycin. ----- Conclusion and implications: The hybrid derivatives described here represent excellent antimalarial drug candidates with the potential for clinical use in malaria therapy

A novel class of fast‐acting antimalarial agents: Substituted 15‐membered azalides

Background and purpose: Efficacy of current antimalarial treatments is declining as a result of increasing antimalarial drug resistance, so new and potent antimalarial drugs are urgently needed. Azithromycin, an azalide antibiotic, was found useful in malaria therapy, but its efficacy in humans is low. ----- Experimental approach: Four compounds belonging to structurally different azalide classes were tested and their activities compared to azithromycin and chloroquine. in vitro evaluation included testing against sensitive and resistant Plasmodium falciparum, cytotoxicity against HepG2 cells, accumulation and retention in human erythrocytes, antibacterial activity, and mode of action studies (delayed death phenotype and haem polymerization). in vivo assessment enabled determination of pharmacokinetic profiles in mice, rats, dogs, and monkeys and in vivo efficacy in a humanized mouse model. ----- Key results: Novel fast-acting azalides were highly active in vitro against P. falciparum strains exhibiting various resistance patterns, including chloroquine-resistant strains. Excellent antimalarial activity was confirmed in a P. falciparum murine model by strong inhibition of haemozoin-containing trophozoites and quick clearance of parasites from the blood. Pharmacokinetic analysis revealed that compounds are metabolically stable and have moderate oral bioavailability, long half-lives, low clearance, and substantial exposures, with blood cells as the preferred compartment, especially infected erythrocytes. Fast anti-plasmodial action is achieved by the high accumulation into infected erythrocytes and interference with parasite haem polymerization, a mode of action different from slow-acting azithromycin. ----- Conclusion and implications: The hybrid derivatives described here represent excellent antimalarial drug candidates with the potential for clinical use in malaria therapy