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Despite the continuing global crisis caused by coronavirus disease 2019 (COVID‐19), there is still no effective treatment. Therefore, we designed and synthesized a novel series of 2‐benzylaminoquinazolin‐4(3H)‐one derivatives and demonstrated that they are effective against SARS‐CoV‐2. Among the synthesized derivatives, 7‐chloro‐2‐(((4‐chlorophenyl)(phenyl)methyl)amino)quinazolin‐4(3H)‐one (Compound 39) showed highest anti‐SARS‐CoV‐2 activity, with a half‐maximal inhibitory concentration value greater than that of remdesivir (IC50 = 4.2 μM vs. 7.6 μM, respectively), which gained urgent approval from the U.S. Food and Drug Administration. In addition, Compound 39 showed good results in various assays measuring metabolic stability, human ether a‐go‐go, Cytochromes P450 (CYPs) inhibition, and plasma protein binding (PPB), and showed better solubility and pharmacokinetics than our previous work. [ABSTRACT FROM AUTHOR]

[Display omitted] Despite the rising threat of fatal coronaviruses, there are no general proven effective antivirals to treat them. 2-Aminoquinazolin-4(3 H)-one derivatives were newly designed, synthesized, and investigated to show the inhibitory effects on SARS-CoV-2 and MERS-CoV. Among the synthesized derivatives, 7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4(3 H)-one (9g) and 2-((3,5-dichlorophenyl)amino)-5-hydroxyquinazolin-4 (3 H)-one (11e) showed the most potent anti-SARS-CoV-2 activities (IC 50 < 0.25 μM) and anti-MERS-CoV activities (IC 50 < 1.1 μM) with no cytotoxicity (CC 50 > 25 μM). In addition, both compounds showed acceptable results in metabolic stabilities, hERG binding affinities, CYP inhibitions, and preliminary PK studies. [ABSTRACT FROM AUTHOR]

New therapies for treating coronaviruses are urgently needed. A series of 4-anilino-6-aminoquinazoline derivatives were synthesized and evaluated to show high anti-MERS-CoV activities. N4 -(3-Chloro-4-fluorophenyl)- N6 -(3-methoxybenzyl)quinazoline-4,6-diamine (1) has been identified in a random screen as a hit compound for inhibiting MERS-CoV infection. Throughout optimization process, compound 20 was found to exhibit high inhibitory effect (IC 50 = 0.157 μM, SI = 25) with no cytotoxicity and moderate in vivo PK properties. [ABSTRACT FROM AUTHOR]

We have reported on aristeromycin (1) and 6′-fluorinated-aristeromycin analogues (2), which are active against RNA viruses such as Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), Zika virus (ZIKV), and Chikungunya virus (CHIKV). However, these exhibit substantial cytotoxicity. As this cytotoxicity may be attributed to 5′-phosphorylation, we designed and synthesized one-carbon homologated 6′-fluorinated-aristeromycin analogues. This modification prevents 5′-phosphorlyation by cellular kinases, whereas the inhibitory activity towards S -adenosyl- l -homocysteine (SAH) hydrolase will be retained. The enantiomerically pure 6 ′ -fluorinated-5 ′ -homoaristeromycin analogues 3a - e were synthesized via the electrophilic fluorination of the silyl enol ether with Selectfluor, using a base-build up approach as the key steps. All synthesized compounds exhibited potent inhibitory activity towards SAH hydrolase, among which 6 ′ -β-fluoroadenosine analogue 3a was the most potent (IC 50 = 0.36 μM). Among the compounds tested, 6 ′ -β-fluoro-homoaristeromycin 3a showed potent antiviral activity (EC 50 = 0.12 μM) against the CHIKV, without noticeable cytotoxicity up to 250 μM. Only 3a displayed anti-CHIKV activity, whereas both 3a and 3b inhibited SAH hydrolase with similar IC 50 values (0.36 and 0.37 μM, respectively), which suggested that 3a 's antiviral activity did not merely depend on the inhibition of SAH hydrolase. This is further supported by the fact that the antiviral effect was specific for CHIKV and some other alphaviruses and none of the homologated analogues inhibited other RNA viruses, such as SARS-CoV, MERS-CoV, and ZIKV. The potent inhibition and high selectivity index make 6 ′ -β-fluoro-homoaristeromycin (3a) a promising new template for the development of antivirals against CHIKV, a serious re-emerging pathogen that has infected millions of people over the past 15 years. [ABSTRACT FROM AUTHOR]