Self-aggregation behaviour of novel thiosemicarbazone drug candidates with potential antiviral activity

Abstract

The present work aimed to gain further insight into the mechanisms governing the aggregation process of 1-indanone thiosemicarbazone drug candidates. Regardless of the relatively low lipophilicity predicted by theoretical calculations, these compounds were very insoluble in water. This performance was especially notorious for methoxylated (and non-N-allylated) derivatives. Thermal analysis revealed that the introduction of one and two CH 3 O-moieties into the aromatic ring increases the T m pronouncedly from 185 1C to 229 1C and 258 1C, respectively. The formation of nano-aggregates in water was suggested by the appearance of a new strong absorption peak at 233-239 nm in the UV spectra. DLS analysis showed the early formation nanoscopic particles (120-300 nm) that undergo a gradual size growth to generate larger submicron structures; these particles remained invisible to the naked eye. The negatively-charged character of the surface was established by zeta potential measurements. These results suggest the generation of an inner hydrophobic ''core'' due to the interaction of highly hydrophobic aromatic rings that is surface-decorated by CQS groups available in a thiolato anionic form. This aggregation mechanism is supported by the fact that methoxylation of the aromatic ring dramatically strengthens the solute-solute affinity, as expressed by the sharp increase in T m and makes these derivatives much more water-insoluble. Finally, overall findings indicate that for these compounds, solubility predictions based on lipophilicity calculations are not reliable and a more thorough characterization is required.

Synthesis, Structural Characterization, and Pro‐apoptotic Activity of 1‐Indanone Thiosemicarbazone Platinum(II) and Palladium(II) Complexes: Potential as Antileukemic Agents

“…tend to form aggregates in water irrespective of the substituent at the N4 position (hydrogen or allyl group). [27] Current findings show that changes to the indanone substituents (R 1 , R 2 and R 3 ) or the N4 substituents on the TSC moiety fail to induce antiproliferative activity. Conversely, platinum(II) and palladium(II) complexes 11-18 derived from compounds 1 and 8, showed significant antiproliferative and cytotoxic activity in this cell line.…”

Novel 1-indanone Thiosemicarbazone Antiviral Candidates: Aqueous Solubilization and Physical Stabilization by Means of Cyclodextrins

“…Phase diagrams were prepared by plotting the TSC concentration in the system versus the final CD concentration. The TSC concentration in the complex was determined by UV spectrophotometry (see below) (21). From these data, a solubility factor (F) was calculated according to Eq.…”

“…PMs were employed to evaluate the intrinsic sensitivity of a technique to detect the TSC when included in the complex and contained a TSC/CD weight ratio identical to that of the complex. TSCs were quantified by UV spectrophotometry (CARY [1E] UV-visible Spectrophotometer Varian, USA), according to a technique described elsewhere (21). Calibration curves of the different TSCs were built with water:dimethyl sulfoxide (DMSO) (98:2) solutions in the 7.5-75.0 μM concentration range.…”

“…However, TSCs display extremely low aqueous solubility and precipitate rapidly in the culture medium, leading to unreliable antiviral half maximal inhibitory concentration (IC 50 ) data (17). In a recent study, we reported for the first time on the self-aggregation behavior of TSCs in water (21). In this context, the investigation of an appropriate drug carrier that improves the aqueous solubility of TSCs and prevents their self-aggregation remains a key stage towards the comprehensive evaluation of their antiviral activity in hepatitis B (HBV) and HCV cell constructs.…”

“…1a). They were synthetized and purified as depicted elsewhere (21). Alpha-CD (Cavamax® W 6 ; α-CD), gamma-CD ( (33).…”