Enhanced In Vitro Antiviral Activity of Hydroxychloroquine Ionic Liquids against SARS-CoV-2

Abstract

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.

Ionic Liquids: New Forms of Active Pharmaceutical Ingredients with Unique, Tunable Properties

“…API-ILs have been prepared from Alzheimer’s and Parkinson’s disease medication, antibiotics, anticancer drugs, antibacterial and antifungal drugs, antihistamine and calcium channel blockers, numerous antimalarial APIs, antivirals, arthritis drugs, beta blockers, drugs for diabetes, gastrointestinal disorders, hyperkalemia, local anesthesia, pain relievers, multiple respiratory disorder medications, supplements, and vitamins, among others. They have been made from compounds such as dextro­methorphan, halofantrine, , hydroxy­chloroquine, rotigotine, ketoprofen, diclophenac, nalidixic acid, donepezil, , rivastigmine, salicylic acid, , and many others. As of January 2023, a Sci-Finder search on the term “API-ILs” provided 98 patents, 2177 research papers, and 289 reviews in which API-ILs were a central theme.…”

Unlocking the Anticancer Potential of Ionic Liquids

“…Faı ´sca et al [57] have reported the repurposing of the antimalarial drug, hydroxychloroquine (HCQ), as an efficient antiviral treatment for SARS-CoV-2, using the dicationic family of ILs to enhance the physicochemical properties. N 4 Yuan et al [58] have studied the use of cholinium-amino acid-based ILs (CHAAILs) to improve the solubility and permeation of poorly soluble drugs.…”

“…Faísca et al. 57 have reported the repurposing of the antimalarial drug, hydroxychloroquine (HCQ), as an efficient antiviral treatment for SARS‐CoV‐2, using the dicationic family of ILs to enhance the physicochemical properties. N 4 ‐(7‐chloroquinolin‐4yl)‐N 1 ‐ethyl‐N 1 ‐(2‐hydroxethyl)pentane‐1,4‐diaminium bis(methanesulfonate) [HCQH 2 ][C 1 SO 3 ] 2 and N 4 ‐(7‐chloroquinolin‐4yl)‐N 1 ‐ethyl‐N 1 ‐(2‐hydroxethyl)pentane‐1,4‐diaminium bis((2S,3R,4S,5S)‐2,3,4,5,6 pentahydroxyhexanoate [HCQH 2 ][GlcCOO] 2 had water solubility and LogP values comparable to other tested HCQ‐ILs that did not demonstrate any increase in antiviral activity.…”

Synthesis and Behavior of Hexamethylenetetramine-Based Ionic Liquids as an Active Ingredient in Latent Curing Formulations with Ethylene Glycol for DGEBA

“…On the other hand, anions of ionic liquids can be both organic and inorganic, and their nature significantly affects the properties of the entire compound. The most important feature of this group of compounds is undoubtedly an extremely wide range of applications, in which the following should be distinguished: (i) dissolution and processing of biomass [ 3 , 4 , 5 ], (ii) catalytic reactions [ 6 , 7 , 8 ], (iii) active ingredients in pharmaceutical preparations [ 9 , 10 ] or (iv) design of polymerizable monomers intended for modern material solutions [ 11 , 12 , 13 ]. The wide area of application of ionic liquids is due to their properties, among which the following should be mentioned: high thermal stability [ 14 ], high electrochemical window [ 15 ], low volatility [ 16 ] and flammability [ 17 ].…”