Darko Filic

Synthesis and biological activity of 4″-O-acyl derivatives of 14- and 15-membered macrolides linked to ω-quinolone-carboxylic unit

The synthesis and antimicrobial activity of a new class of macrolide antibiotics which consist of a macrolide scaffold and a quinolone unit covalently connected by an appropriate linker are described. Optimization of several synthetic steps and structural properties of lead compound 26 are discussed. Promising antibacterial properties of this compound and some of its analogues are reported.

Synthesis, activity and pharmacokinetics of novel antibacterial 15-membered ring macrolones.

Synthesis, antibacterial activity and pharmacokinetic properties of a novel class of macrolide antibiotics-macrolones-derived from azithromycin, comprising oxygen atom(s) in the linker and either free or esterified quinolone 3-carboxylic group, are reported. Selected compounds showed excellent antibacterial potency towards key erythromycin resistant respiratory pathogens. However, the majority of compounds lacked good bioavailability. The isopropyl ester, compound 35, and a macrolone derivative with an elongated linker 29 showed the best oral bioavailability in rats, both accompanied with an excellent overall microbiology profile addressing inducible and constitutive MLSb as well as efflux mediated macrolide resistance in streptococci, while compound 29 is more potent against staphylococci.

Synthesis, NMR and X-ray structure analysis of macrolide aglycons

Macrolide aglycons (E)-9-hydroxyimino-6-O-methylerythronolide A (4), 9a-aza-9-deoxo-9,9-dihydro-9a,11-O-dimethyl-9a-homoerythronolide A (5) and 9a-aza-9-deoxo-9,9-dihydro-9a-homoerythronolide A (6) were prepared by multistep syntheses. A conformational study of these new macrolide aglycons was performed using single crystal X-ray crystallography to gain information about the solid state, while a combination of NMR spectroscopy and molecular modelling was employed to study the solution structures. The crystal structures were found to be stabilised by a complex network of hydrogen bonds and van der Waals interactions. To some extent, the same building motif of infinite molecular chains held together by O–H···O hydrogen bonds was present in the crystal structure of all three compounds. Thorough analysis and comparison of the obtained solid state structures with their solution counterparts showed no significant differences between them, confirming the constrained flexibility of the macrocyclic ring. Moreover, in all three compounds, in both solution and solid state, the macrolactone ring adopts energetically more favoured folded-out conformations.

Supramolecular structures of three isomeric 4-(methylphenylamino)pyridine-3-sulfonamides.

The structures of the three title isomers, namely 4-(2-methylanilino)pyridine-3-sulfonamide, (I), 4-(3-methylanilino)pyridine-3-sulfonamide, (II), and 4-(4-methylanilino)pyridine-3-sulfonamide, (III), all C(12)H(13)N(3)O(2)S, differ in their hydrogen-bonding arrangements. In all three molecules, the conformation of the 4-aminopyridine-3-sulfonamide moiety is conserved by an intramolecular N-H...O hydrogen bond and a C-H...O interaction. In the supramolecular structures of all three isomers, similar C(6) chains are formed via intermolecular N-H...N hydrogen bonds. N-H...O hydrogen bonds lead to C(4) chains in (I), and to R(2)(2)(8) centrosymmetric dimers in (II) and (III). In each isomer, the overall effect of all hydrogen bonds is to form layer structures.

Classification of torasemide based on the Biopharmaceutics Classification System and evaluation of the FDA biowaiver provision for generic products of CLASS I drugs.

The biopharmaceutical properties of an in‐house developed new crystal modification of torasemide (Torasemide N) were investigated in comparison with the most well known crystal modification form of torasemide (Torasemide I) in order to classify the drug according to the Biopharmaceutics Classification System (BCS), and to evaluate the data in line with current US Food and Drug Administration (FDA) guidance (with biowaiver provision for Class I drugs) to determine if the biowaiver provision could be improved. The solubility profiles of Torasemide I and Torasemide N were determined, and tablets prepared from both forms of the drug were studied for in‐vitro release characteristics in media recommended by the current FDA guidance for biowaiver of generic products, and in other media considered more appropriate for the purpose than the ones recommended by the FDA. Two separate bioequivalence studies in healthy humans (following oral administration) were performed with two test products (both prepared from Torasemide I) against a single reference product (prepared from Torasemide N). The absorption profiles of the drug from the tablets were determined by deconvolution for comparison with the in‐vitro release profiles to determine the appropriateness of some dissolution media for predicting in‐vivo performance and to determine the comparative rate and extent of absorption. The drug was absorbed from the tested products quickly and almost completely (about 95% within 3.5 h of administration). However, one test product failed to meet the bioequivalence criteria and had a significant initial lower absorption rate profile compared with the reference product (P ≤ 0.05), whereas the other product was bioequivalent and had a similar absorption profile to the reference product. A dissolution medium at pH 5.0, in which torasemide has minimum solubility, was found to be more discriminatory than the media recommended by the FDA. Torasemide has been classified as a Class I drug according to the BCS up to a maximum dose of 40 mg and the data suggest that the current FDA guidance could be improved by giving more emphasis to selection of appropriate dissolution media than is given in its current form for approving biowaiver to generic products of Class I drugs.