Potent Lipophilic Melatoninergic x-fluoro-y-methoxy Substituted Phenylalkylamides: Molecular Dynamics Calculations and in vitro Modified Release in Aqueous Media from Tablet Formulations.

INTRODUCTION: We report herein on the design and development of matrix tablets containing potent synthetic melatonin (MLT) receptor analogues, the x-fluoro-y-methoxy substitiuted phenylalkylamides (compounds I-IV), the preparation and melatoninergic potency of which was recently communicated. > Methods: The presence of the fluorine atom in compounds I-IV, besides not affecting their binding affinity, compared to the pineal hormone melatonin, it also slows down their metabolism, which is a major drawback of MLT. However, as fluorine increases the lipophilicity, solid pharmaceutical formulations of I-IV, involving the appropriate biopolymers for their modified release in aqueous media, were developed in the context of the present work. > Results: The release profile of analogues I-IV was found to be similar to that of MLT and also of the commercially available drug, Circadin®. Some of these systems are suitable for dealing with sleep onset problems, whilst others for dealing with combined sleep onset/sleep maintenance problems. > Conclusion: Apart from the nature and relevant content of the formulants used, this bimodal release profile of the new analogues depends, to a large extent, on the diverse structural arrangement of their side chains in space, as nicely demonstrated by the molecular dynamics calculations, conducted in the context of this study. >.

Synthesis and Testing of Analogs of the Tuberculosis Drug Candidate SQ109 against Bacteria and Protozoa: Identification of Lead Compounds against Mycobacterium abscessus and Malaria Parasites.

SQ109 is a tuberculosis drug candidate that has high potency against Mycobacterium tuberculosis and is thought to function at least in part by blocking cell wall biosynthesis by inhibiting the MmpL3 transporter. It also has activity against bacteria and protozoan parasites that lack MmpL3, where it can act as an uncoupler, targeting lipid membranes and Ca2+ homeostasis. Here, we synthesized 18 analogs of SQ109 and tested them against M. smegmatis, M. tuberculosis, M. abscessus, Bacillus subtilis, and Escherichia coli, as well as against the protozoan parasites Trypanosoma brucei, T. cruzi, Leishmania donovani, L. mexicana, and Plasmodium falciparum. Activity against the mycobacteria was generally less than with SQ109 and was reduced by increasing the size of the alkyl adduct, but two analogs were ∼4-8-fold more active than SQ109 against M. abscessus, including a highly drug-resistant strain harboring an A309P mutation in MmpL3. There was also better activity than found with SQ109 with other bacteria and protozoa. Of particular interest, we found that the adamantyl C-2 ethyl, butyl, phenyl, and benzyl analogs had 4-10× increased activity against P. falciparum asexual blood stages, together with low toxicity to a human HepG2 cell line, making them of interest as new antimalarial drug leads. We also used surface plasmon resonance to investigate the binding of inhibitors to MmpL3 and differential scanning calorimetry to investigate binding to lipid membranes. There was no correlation between MmpL3 binding and M. tuberculosis or M. smegmatis cell activity, suggesting that MmpL3 is not a major target in mycobacteria. However, some of the more active species decreased lipid phase transition temperatures, indicating increased accumulation in membranes, which is expected to lead to enhanced uncoupler activity.