Enhanced In Vitro Antiviral Activity of Hydroxychloroquine Ionic Liquids against SARS-CoV-2
Francisco Faísca, Vanessa Correia, Željko Petrovski, Luís C Branco, Helena Rebelo-De-Andrade, Miguel M Santos
Pharmaceutics, doi:10.3390/pharmaceutics14040877
The development of effective antiviral drugs against SARS-CoV-2 is urgently needed and a global health priority. In light of the initial data regarding the repurposing of hydroxychloroquine (HCQ) to tackle this coronavirus, herein we present a quantitative synthesis and spectroscopic and thermal characterization of seven HCQ room temperature ionic liquids (HCQ-ILs) obtained by direct protonation of the base with two equivalents of organic sulfonic, sulfuric and carboxylic acids of different polarities. Two non-toxic and hydrophilic HCQ-ILs, in particular, [HCQH 2 ][C 1 SO 3 ] 2 and [HCQH 2 ][GlcCOO] 2 , decreased the virus-induced cytopathic effect by two-fold in comparison with the original drug, [HCQH 2 ][SO 4 ]. Despite there being no significant differences in viral RNA production between the three compounds, progeny virus production was significantly affected (p < 0.05) by [HCQH 2 ][GlcCOO] 2 . Overall, the data suggest that the in vitro antiviral activities of the HCQ-ILs are most likely the result of specific intra-and intermolecular interactions and not so much related with their hydrophilic or lipophilic character. This work paves the way for the development of future novel ionic formulations of hydroxychloroquine with enhanced physicochemical properties.
(9) resulted in more than 60% inhibition of CPE at 10 µ M (70.5%, 60.8% and 62.5%, respectively), which contrasted with the remaining compounds, including 1 (lower than 20%; see Figure 3A ). The EC50 values of these three novel formulations (8.1, 8.9 and 8.5 µ M, respectively) were significantly lower than those of all other HCQ-ILs and differed by ca. two-fold from the EC50 of 1 (16.5 µ M) (Table 5 ). No significant differences in EC90 were observed between the seven novel HCQ-ILs and 1, with all values being registered beyond 20 µM. Table 5 . The 50% (EC50) and 90% (EC90) effective concentrations of [HCQH2][SO4] (1) and HCQ-ILs 3-9 for the inhibition of the virus-induced cytopathic effect (CPE) on Vero E6 cells infected with SARS-CoV-2. The results are presented as the mean of three independent experiments with triplicate measurements. The 95% confidence interval (CI) is indicated in a separate column. SI represents the CC50/EC50 selectivity ratio. No inhibitory effects were found for the anions. Significant differences (SIG diff.) were evaluated using a one-way analysis of variance (ANOVA) followed by Tukey's multiple comparison test. A p-value < 0.05 was considered significant, with * p < 0.05, ** p < 0.01, *** p < 0.001. The enhanced antiviral activity of 3 and 9 in this initial screening doubled their SI ratio (26.9 and 23.1, respectively) in comparison with 1 (13.0) (Table 5 ), leading them to be identified as the most promising HCQ-ILs. Hence, these..
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"abstract": "<jats:p>The development of effective antiviral drugs against SARS-CoV-2 is urgently needed and a global health priority. In light of the initial data regarding the repurposing of hydroxychloroquine (HCQ) to tackle this coronavirus, herein we present a quantitative synthesis and spectroscopic and thermal characterization of seven HCQ room temperature ionic liquids (HCQ-ILs) obtained by direct protonation of the base with two equivalents of organic sulfonic, sulfuric and carboxylic acids of different polarities. Two non-toxic and hydrophilic HCQ-ILs, in particular, [HCQH2][C1SO3]2 and [HCQH2][GlcCOO]2, decreased the virus-induced cytopathic effect by two-fold in comparison with the original drug, [HCQH2][SO4]. Despite there being no significant differences in viral RNA production between the three compounds, progeny virus production was significantly affected (p < 0.05) by [HCQH2][GlcCOO]2. Overall, the data suggest that the in vitro antiviral activities of the HCQ-ILs are most likely the result of specific intra- and intermolecular interactions and not so much related with their hydrophilic or lipophilic character. This work paves the way for the development of future novel ionic formulations of hydroxychloroquine with enhanced physicochemical properties.</jats:p>",
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