Effect of β-cyclodextrin on the CO release kinetics and antimicrobial activity of [NEt₄][Mo(CO)₅Br]

abstract

In the present work the possibility of improving the solubility, bioavailability and bactericidal activity of the carbon monoxide releasing molecule (CORM) [Mo(CO)(5)Br](-) (as its tetraethylammonium salt) (1) by solvent-free co-grinding with beta-cyclodextrin (beta CD) in a planetary ball mill was investigated. Data obtained by FT-IR spectroscopy, Raman spectroscopy, powder X-ray diffraction and thermogravimetric analysis showed that, other than a small decrease in the crystallinity of 1, the co-grinding process produced a finely dispersed physical mixture of crystalline CORM and crystalline excipient. The aqueous solubility of 1 in the 1-beta CD product was enhanced with respect to sparingly soluble pure 1, which might be ascribed to increased wettability and a CD-CORM interaction in solution. Investigation of the CO release kinetics by the standard myoglobin assay showed that the half-life of CO release increased from ca. 6 min for 1 to ca. 19 min for 1-beta CD, while the number of equivalents released decreased from 3.2 to 1.8. The antibacterial properties of 1 and 1-beta CD were evaluated using the broth microdilution method to determine minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against the model Gram-negative bacterium, Escherichia coli. The compounds showed similar growth inhibitory (MIC values of 200 mu M) and bactericidal (MBC/MIC approximate to 2) effects. Bacterial viability assays corroborated the MBC/MIC studies, showing 3 logs (99.9% of relative light units - RLU) reduction in viable cell count after 15 min exposure to 2 x MIC. Although the CORM-CD system displays a lengthening of the half-life of CO release and a decrease in the CO release efficiency relative to 1, the co-grinding with beta CD does not affect the bactericidal activity of the CORM. Overall, the beta CD could be a suitable excipient for the development of immediate-release formulations of CORMs like the pentacarbonyl complex 1.

keywords

CARBON-MONOXIDE; MOLECULES; EXCIPIENTS; TOXICITY; DELIVERY; BIOLOGY

subject category

Chemistry

authors

Monteiro, RP; Calhau, IB; Gomes, AC; Pereira, C; Vieira, C; Faustino, MAF; Almeida, A; Pillinger, M; Romao, CC; Gonçalves, IS

Groups

G1 - Porous Materials and Nanosystems

Projects

CICECO - Aveiro Institute of Materials (UIDB/50011/2020)

CICECO - Aveiro Institute of Materials (UIDP/50011/2020)

Associated Laboratory CICECO-Aveiro Institute of Materials (LA/P/0006/2020)

acknowledgements

This work was developed within the scope of the project CICECO-Aveiro Institute of Materials (UIDB/50011/2020, UIDP/50011/2020 and LA/P/0006/2020) , LAQV-REQUIMTE (UIDB/50006/2020 and UIDP/50006/2020) , and CESAM (UIDB/50017/202 and UIDP/50017/2020) , financed by national funds through the FCT (Fundacao para a Ciencia e a Tecnologia) /MCTES (Ministerio da Ciencia, Tecnologia e Ensino Superior) (PIDDAC) . I.B.C. (ref. 2021.05953.BD) , R.P.M. (ref. 2020.04758.BD) , and C.V. (ref. SFRH/BD/150358/2019) are grateful to the FCT and the European Social Fund (ESF) for PhD grants. A.C.G. (CEECIND/02128/2017) thanks the FCT/MCTES for funding through the Individual Call to Scientific Employment Stimulus.