Discovery of 2-Phenylquinolines with Broad-Spectrum Anti-coronavirus Activity

Abstract

A selection of compounds from a proprietary library, based on chemical diversity and various biological activities, was evaluated as potential inhibitors of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in a phenotypic-based screening assay. A compound based on a 2-phenylquinoline scaffold emerged as the most promising hit, with EC 50 and CC 50 values of 6 and 18 μM, respectively. The subsequent selection of additional analogues, along with the synthesis of ad hoc derivatives, led to compounds that maintained low μM activity as inhibitors of SARS-CoV-2 replication and lacked cytotoxicity at 100 μM. In addition, the most promising congeners also show pronounced antiviral activity against the human coronaviruses HCoV-229E and HCoV-OC43, with EC 50 values ranging from 0.2 to 9.4 μM. The presence of a 6,7-dimethoxytetrahydroisoquinoline group at the C-4 position of the 2-phenylquinoline core gave compound 6g that showed potent activity against SARS-CoV-2 helicase (nsp13), a highly conserved enzyme, highlighting a potentiality against emerging HCoVs outbreaks.

Coronaviruses SARS-CoV, MERS-CoV, and SARS-CoV-2 helicase inhibitors: a systematic review of in vitro studies

“… 26 , 27 , 33 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 As a result, five studies were found to fit the inclusion criteria of this review. 78 , 79 , 80 , 81 , 82 These were reviewed by the two researchers who mutually agreed to include them into the review. The final thirty-one studies describing the in vitro assays of 309 chemical compounds on the unwinding and ATPase activities of SARS-CoV, MERS-CoV, and SARS-CoV-2 helicases were used for the full-text analysis and extraction of data of interest ( Fig.…”

“…Only ten studies reported the kinetic parameters of the enzymes used in the assays. 26 , 27 , 56 , 64 , 72 , 73 , 77 , 78 , 79 , 80 These studies estimated the Michaelis-Menten constants ( k cat ) and turnover numbers ( K m ) of the ATP and double-stranded nucleic acid substrates of the tested helicases. Kinetic parameters of the double-stranded nucleic acid are estimated by measuring the rate of Forster resonance energy transfer (FRET) signal increase as a result of the separation of fluorophore-labeled double-stranded nucleic acids ( Table S2 ).…”

Potential COVID-19 Therapies from Computational Repurposing of Drugs and Natural Products against the SARS-CoV-2 Helicase

“…Another group established biochemical assays for SARS-CoV-2 nps13-associated enzyme activities on RNA unwinding and 5′-triphosphatase activity and used these to screen a small in-house library of natural compounds identifying myricetin, quercetin, kaempferol, and flavanone as inhibitors of RNA unwinding activity and licoflavone C as an inhibitor of both helicase activities [ 61 ]. A compound based on a 2-phenylquinoline scaffold was shown to have potent in vitro activity against SARS-CoV-2 helicase [ 62 ].…”

Transition‐Metal‐Free Synthesis of Functionalized Quinolines by Direct Conversion of β‐O‐4 Model Compounds

“…For example, 2-phenylquinoline 3 d is proved to be a useful natural gastroprotective agent, [22] and other 2-phenylquinoline scaffolds are reported as privileged structures to impart SARS-CoV-2 inhibitory activity. [23] In addition, based on the above-described route, we also established an interesting protocol for the synthesis of graveolinine analogue 18 (Scheme S2), a precursor for different antibacterial, spasmolytic and antitumor drugs, [24] from a lignin β-O-4 model compound to give 33 % overall yield. On the other hand, guaiacol and its derivatives are also valuable precursors for the synthesis of various flavorants, pesticides, and dyes.…”