ABSTRACT
Despite being a preventable and curable disease, Tuberculosis (TB) is the world's top infectious killer. Development of new drugs is urgently needed. In this work, the synthesis and characterization of new silver(I) complexes, that include N'-[(E)-(pyridine-2-ylmethylene)pyrazine-2-carbohydrazide, HPCPH, as main ligand and substituted aryl-phosphines as auxiliary ligands, is reported. HPCPH was synthesized from pyrazinoic acid, the active metabolite of the first-line antimycobacterial drug pyrazinamide. Complexes [Ag(HPCPH)(PPh3)2]OTf (1), [Ag(HPCPH)((P(p-tolyl)3)2]OTf (2) and [Ag(HPCPH)(P(p-anisyl)3)2]OTf (3) were characterized in solid state and in solution by elemental analysis and FTIR and NMR spectroscopies (OTftriflate). Crystal structures of (1,2) were determined by XRD. The Ag atom is coordinated to azomethine and pyridine nitrogen atoms of HPCPH ligand and to the phosphorous atom of each aryl-phosphine co-ligand. Although HPCPH did not show activity, the Ag(I) compounds demonstrated activity against Mycobacterium tuberculosis (MTB), H37Rv strain, and multi-drug resistant clinical isolates (MDR-TB). Globally, results showed that the compounds are not only effective against the sensitive strain, but are more potent against MDR-TB than antimycobacterial drugs used in therapy. The compounds showed low to moderate selectivity index values (SI) towards the bacteria, using MRC-5 cells (ATCC CCL-171) as mammalian cell model. Interaction with DNA was explored to get insight into the potential mechanism of action against the pathogen. No significant interaction was detected, allowing to discard this biomolecule as a potential molecular target. Compound 1 was identified as a hit compound (MIC90 2.23 µM; SI 4.4) to develop further chemical modifications in the search for new drugs.
Subject(s)
Antitubercular Agents , Coordination Complexes , Hydrazines , Mycobacterium tuberculosis/growth & development , Silver , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Cell Line , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Drug Evaluation, Preclinical , Humans , Hydrazines/chemistry , Hydrazines/pharmacology , Silver/chemistry , Silver/pharmacologyABSTRACT
Defibrillation of bacterial cellulose by ultra-refining was efficient to release nanofibers (BCNF) which were spray dried with the matrices formers mannitol (MN), maltodextrin or hydroxypropylmethylcellulose. The best microsystem comprised the association of BCNF and MN, so the selected microparticles were loaded with diclofenac sodium or caffeine. Depending on the proportion of BCNF, the nanofibers collapse promoted by spray drying can occur onto surface or into microparticles core, leading to different release behaviors. Samples showed pH-dependent drug release, so the microsystem developed with the lowest BCNF concentration showed important trend to gastroresistance. Caffeine was spray dried as a free drug and for this reason it was devoid of any control over release rates. The set of results showed BCNF can be considered an interesting and potential pharmaceutical excipient for lipophilic drugs. Beyond that, BCNF association with MN can lead to novel enteric drug delivery systems based on natural polymers.
