Antimicrobial and antiviral sulfur containing glycerol monoester derivatives
Inventors
Reardan, Dayton T. • Brennan, Paul • Schlievert, Patrick
Assignees
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Publication Number
US-11873272-B2
Publication Date
2024-01-16
Expiration Date
Abstract
The disclosure relates generally novel sulfur containing glycerol mono-ester derivatives and methods useful for treating gram positive, gram negative, fungal and envelope viral infections in a patient.
Core Innovation
The invention relates to sulfur-containing glycerol mono-ester derivatives defined by Formula (I), including embodiments where X is S and where substituents R1–R4 and/or R2–R3 are varied according to the definitions of the general formula. The described derivatives include glycerol thionomonolaureate (SGML) and glycerol dithionomonolaureate (S2GML), including stereoisomer variants (R)-SGML/(S)-SGML and (R)-S2GML/(S)-S2GML.
The document addresses the problem that glycerol monolaureate (GML) has limits in efficacy for antimicrobial/antiviral applications, motivating sulfur-containing glycerol mono-ester derivatives intended to improve or extend activity. It further frames the invention by describing compound definitions, extensive embodiment language, and chemical structures associated with the derivatives, with esterase activity included in the mechanistic framing.
The invention also includes pharmaceutical compositions comprising the sulfur-containing glycerol mono-ester derivatives and therapeutic use for treating infections. Treatment coverage is explicitly mapped across infection classes including gram-positive infections and gram-negative infections, fungal infections, and envelope viral infections, with specific examples such as viral respiratory infections, viral gastrointestinal infections, hepatitis-related infections, neurologic infections, and skin or placenta-fetal infections.
Claims Coverage
The document provides one independent claim directed to compounds of Formula (I) with X fixed to sulfur (S). The independent-claim coverage centers on structural constraints for R1–R4 and optional formation of a 3- to 5-membered aliphatic carbocyclic ring from R2 and R3, plus the option for pharmaceutically acceptable salts.
Sulfur-containing compound of formula (I)
A compound of Formula (I) wherein R1 is selected from alkyl, alkenyl, and alkynyl; R2 and R3 are independently selected from hydrogen, COR4, —CON(H)R4, —CO2R4, or P(O)(OR4)2, or taken together with the carbon to which they are attached form a 3- to 5-membered aliphatic carbocyclic ring; R4 is H, alkyl, alkenyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl; and X is S; or a pharmaceutically acceptable salt thereof.
Claim coverage is anchored on a Formula (I) sulfur (X=S) glycerol mono-ester derivative scaffold with defined allowable substituent classes for R1 and R2/R3 and allowable R4 groups. The dependent claim set refines substituent choices, specifies particular substituent types, includes structural embodiments shown in embedded images, and extends into pharmaceutical compositions and treatment methods for specified infection classes.
Stated Advantages
The sulfur-containing glycerol mono-ester derivatives are intended to improve or extend antimicrobial/antiviral activity relative to glycerol monolaureate (GML), which is described as having limits in efficacy.
SGML/S2GML show greater killing versus GML in antibacterial activity results.
SGML/S2GML show reduced esterase hydrolysis versus GML in esterase/lipase resistance testing.
Documented Applications
Treating antimicrobial/antiviral infections, including gram-positive and gram-negative infections.
Treating fungal infections, including ringworm, vaginal candidiasis, blastomycosis, coccidioidomycosis, cryptococcus, histoplasmosis, paracoccidioidomycosis, aspergillosis, candidiasis, Candida auris, pneumocystis pneumonia, talaromycosis, mycetoma, sporotrichosis.
Treating envelope viral infections, including viral respiratory infections and examples listed such as influenza, coronaviruses, SARS-CoV-2, noroviruses, rotaviruses, Zika virus, rubella virus, cytomegalovirus, rabies virus, and West Nile virus.
Treating viral infections with enumerated disease examples listed in the document, including meningitis, polio, and other listed virus-associated conditions.
Treating skin infections including staphylococcus aureus and wart/rash categories as described in the document.
Treating urinary tract infections (UTIs), including cystitis, urethritis, prostatitis, and pyelonephritis, including herpes simplex virus associated UTI as listed.
Antibacterial activity testing and comparison of GML versus SGML and S2GML against Staphylococcus aureus (including TSS strains), E. coli, and additional microbes.
Antibacterial/biological activity assessment including esterase/lipase resistance testing (esterase/lipase assay) to support conclusions regarding relative killing and reduced esterase hydrolysis versus GML.
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