Broad spectrum antiviral compositions and methods
Inventors
Remiszewski, Stacy • Chiang, Lillian W. • MURPHY, EAIN ANTHONY • Sun, Qun • Kayser, Frank • Fink, Sarah Jocelyn
Assignees
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Publication Number
US-12459935-B2
Publication Date
2025-11-04
Expiration Date
Abstract
Novel thiazole- and isoquinoline-containing compounds are presented that are useful for treating and/or preventing broad-spectrum viral infections. Methods of treating and/or preventing broad-spectrum viral infections are also presented. These compounds have shown inhibition of HCMV, influenza viruses, Zika virus, BK Virus and RSV replication in cell-based assays.
Core Innovation
The document describes broad-spectrum antiviral compounds defined by Formula I, including multiple alternative structural embodiments via Formulas II–VII. The compounds contain a substituted scaffold in which X1 and X2 are N and S, and X3 and X4 are independently selected from C and N, with optional substitution patterns and additional structural variability through substituent groups R1–R12.
A central aspect is the defined relationship between the substituent variables and the substituted aryl or cycloalkyl portions used to construct the Formula I compound. The definitions specify how R1 and R2 are selected as H versus a 5- or 6-membered aryl or cycloalkyl with ring heteroatoms, and how R3 and R4 are selected from enumerated functional substituents and ring-structure options, with a condition that R3 and R4 are not both H and that at least one of them is selected from a specified group. The substituent groups R5, R6, R7, R8, and R12 are also constrained to defined sets of allowed moieties.
The document also describes therapeutic and virus-control use, including treating and preventing infections by diverse viruses explicitly including HCMV, influenza A, Zika virus, BK virus, RSV, coronaviruses, parainfluenza viruses, and adenovirus. It further describes methods of inhibiting virus replication or virus production by contacting virus-infected cells with a virus production inhibiting amount of the Formula I compounds, and it describes selecting specific embodiments through the enumerated substituent options within the Formula I framework.
Claims Coverage
The independent claim coverage centers on one method claim directed to inhibiting virus production by contacting a virus-infected cell with a composition containing a Formula I compound. The inventive scope is defined by extensive structural limitations on X1/X2, X3/X4, R1/R2, and R3–R12, with dependent claims narrowing substituent selections and optionally adding a co-administered antiviral agent.
Contacting a virus-infected cell with a virus production inhibiting amount of Formula I
A method of inhibiting virus production by contacting a virus-infected cell with a virus production inhibiting amount of a composition comprising a compound of Formula I, with structural constraints on X1, X2, X3, X4, and R1–R12, including the inclusion of pharmaceutically acceptable salts or solvates.
X1/X2 defined as N and S, and X3/X4 defined from C and N
One of X1 and X2 is N and the other is S, and X3 and X4 are independently selected from C and N, with optional methyl, ethyl, propyl, i-propyl, or n-propyl substitution when X3 is C.
R1 and R2 aryl or cycloalkyl selection with ring heteroatoms and constrained substituents
One of R1 and R2 is H and the other is a 5- or 6-membered aryl or cycloalkyl with 0 to 3 ring heteroatoms independently selected from N and O and substituted with 0 to 3 groups from the enumerated alkyl, alkoxy, and cycloalkyl options; alternatively, R1 and R2 together form a substituted 5- or 6-membered aryl or cycloalkyl under the same ring-heteroatom and substituent limitations.
R3 and R4 enumerated substituent constraints with not-both-H requirement
R3 and R4 are selected from enumerated substituent groups including halo, —C≡CH, —C≡N, —OH, —OCF3, —OCHF2, C1-4 alkoxy, —SO2(C1-6 alkyl), —N(CH3)2, —C(O)NH2, —NHSO2R7, —C(O)NR7R8, and ring structures with 0 to 3 ring heteroatoms, provided that at least one of R3 and R4 is selected from the specified group and that R3 and R4 are not both H.
R5, R6, R7, R8, and R12 selection constraints
R5 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, CF3, CH2CF3, and halo; R6 is selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, CF3, CH2CF3, halo, cyclopropylmethyl, and C1-4 alkoxy; R7 and R8 are independently selected from H, C1-6 straight or branched alkyl, C3-6 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl; and R12 is independently selected from H and C1-4 straight or branched alkyl.
The core coverage is a virus production inhibition method based on a highly restricted Formula I compound, with the main inventive features defined by heteroatom selections at X1/X2 and X3/X4, ring-limited and substitution-limited R1/R2 definitions, enumerated R3/R4 substituents with the explicit requirement that R3 and R4 are not both H, and additional constrained selections for R5, R6, R7, R8, and R12.
Stated Advantages
Inhibits virus production in virus-infected cells.
Inhibits viral replication of RSV, Zika virus (strain MR776), and BK virus in cell culture.
Broad-spectrum antiviral activity is described for HCMV, influenza A, Zika virus, BK virus, RSV, coronaviruses, parainfluenza viruses, and adenovirus.
Documented Applications
In vitro antiviral activity assays against human cytomegalovirus (HCMV) and murine-adapted influenza (PR8) using mCherry-tagged viruses, reporting IC50 values for multiple examples.
Inhibiting virus production in a virus-infected cell.
RSV, Zika virus (strain MR776), and BK virus replication inhibition in cell culture using some listed Table 1 compounds.
Treating and preventing infections by HCMV, influenza A, Zika virus, BK virus, RSV, coronaviruses, parainfluenza viruses, and adenovirus.
Inhibiting virus replication or virus production by contacting virus-infected cells with a virus production inhibiting amount of the Formula I compounds.
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