Improvement of Solubility and Antifungal Activity of a New Aminothiophene Derivative by Complexation with 2-Hydroxypropyl-β-cyclodextrin

Abstract

This study aimed to prepare a complex of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and 6CN10, a poorly water soluble 2-aminothiophene derivative with antifungal properties, by freeze-drying technique. The complex was characterized by thermal analysis, infrared/Raman spectroscopy, X-ray diffraction and scanning electron microscopy. In addition, we used the data of the phase solubility study, 1 H, and 2D NMR spectroscopy and molecular modeling in order to investigate the interactions between 6CN10 and HP-β-CD. The apparent solubility of 6CN10 with HP-β-CD increased more than 29 fold. The phase solubility assay in water at 25 ºC showed an A P -type curve, with an apparent stability constant K 1:1 and K 1:2 of 96 and 0.1989 M -1 , respectively. The results of IR, NMR and docking indicate that 6CN10 is able to form complexes with HP-β-CD (1:1 and 1:2 stoichiometric ratios), generating the formation of inclusion and preferably, non-inclusion complexes. The antifungal activity against Cryptococcus neoformans demonstrated the superior performance of the complex (46.66 μg mL -1 ) when compared with the free drug (166.66-333.33 μg mL -1 ). The present study provides useful information for the potential application of complexation with low soluble compounds and about the type of complex formation between 6CN10 and HP-β-CD.

Incorporation of 2-amino-thiophene derivative in nanoparticles: enhancement of antifungal activity

“…Compound 6CN10 was synthesized according to previously published procedures [11], and its chemical structure was confirmed by comparing its 1 H NMR spectrum. 6CN10:HP-β-CD complex was prepared according to the procedure describe in Eleamen et al [15]. Amphotericin B, poly-εcaprolactone, 2-hydroxypropyl-β-cyclodextrin, Tween 80, Mygliol 812, chloramphenicol, and DMSO were purchased from Sigma-Aldrich (Brazil).…”

“…In recent years, our research group demonstrated the potential of 2-amino-thiophene derivatives to inhibit fungal growth [11][12][13][14][15]. In 2011 [11], an analysis of 44 derivatives against clinical isolates of Candida and Cryptococcus strains showed that (i) 2-amino-thiophenes have fungicidal activity; (ii) C. neoformans strains have greater sensitivity to the compounds, and the most promising compound was 2-[(4-nitrobenzylidene)-amino]-4,5,6,7-tetrahydro-4H-benzo[b]thiophene-3-carbonitrile, called 6CN10 ( Fig.…”

“…In 2012 [12], computer-aided drug design (CADD) studies were performed with more than 50 2-amino-thiophene derivatives, including 6CN10; the authors observed that the main factor limiting the antifungal activity of these compounds was their low aqueous solubility. In order to overcome this undesirable characteristic, in 2017 [15], we generated complexes of 6CN10 with 2-hydroxypropyl-βcyclodextrin (HP-β-CD) and observed an increase in anti-Cryptococcus activity of about 3.5 to 7 times, demonstrating improvements in water solubility, and promoting an increase in the antifungal potential of 2-amino-thiophene derivatives.…”

Polyamidoamine Dendrimers for Enhanced Solubility of Small Molecules and Other Desirable Properties for Site Specific Delivery: Insights from Experimental and Computational Studies

“…Many antifungal drugs also suffer from clinical uses hampered by their poor solubility profiles. Several efforts to increase solubility of many antifungal drugs have been carried out over the past years, for example, cyclodextrin has previously been extensively studied as solubility enhancer for many antifungal drugs [ 60 , 61 ] An attempt to improve the solubility of an antifungal drug, amphotericin B ( 23 ), whose clinical use has been hampered by poor water solubility and nephrotoxicity, was done using PAMAM dendrimer [ 51 ]. Amphotericin B ( 23 ), was loaded to PAMAM dendrimer of different generations [ 51 ].…”

Probing Subsistence of Host Guest Inclusion Complexes of Oligosaccharides with Allopurinol for Regulatory Release with the Manifestation of Solvation Consequences

“…This is the real meaning of molecular encapsulation by inclusion complex formation. Taking into account that one, and probably largest, field of practical utilization of CDs is based on their solubilizing capacity (mainly in pharmaceutical industry) due attention must be paid to the above-mentioned, and many other CDrelated, apparent anomalies by solution chemistry [18][19][20][21][22][23][24][25] The goal of this paper is to give comprehensive information about therapeutic effects and the controlled delivery of allopurinol as an antioxidant agent in some diseases including hyperuricemia, renal IRI, nephrotoxicity, gout, contrast-induced nephropathy etc.…”