US 11,697,693 B2
Nitric oxide-releasing alginates as biodegradable antibacterial scaffolds and methods pertaining thereto
Mark H. Schoenfisch, Chapel Hill, NC (US); Mona Jasmine R. Ahonen, Chapel Hill, NC (US); Dakota J. Suchyta, Chapel Hill, NC (US); and Kaitlyn Rose Rouillard, Durham, NC (US)
Assigned to The University of North Carolina at Chapel Hill, Chapel Hill, NC (US)
Filed by The University of North Carolina at Chapel Hill, Chapel Hill, NC (US)
Filed on Jul. 26, 2021, as Appl. No. 17/385,497.
Application 17/385,497 is a division of application No. 16/475,615, granted, now 11,072,668, previously published as PCT/IB2018/050051, filed on Jan. 3, 2018.
Claims priority of provisional application 62/441,742, filed on Jan. 3, 2017.
Claims priority of provisional application 62/483,505, filed on Apr. 10, 2017.
Prior Publication US 2021/0347918 A1, Nov. 11, 2021
Int. Cl. C08B 37/00 (2006.01); A61P 11/12 (2006.01); A61P 31/04 (2006.01); A01N 65/03 (2009.01); A61K 31/734 (2006.01)
CPC C08B 37/0084 (2013.01) [A01N 65/03 (2013.01); A61K 31/734 (2013.01); A61P 11/12 (2018.01); A61P 31/04 (2018.01)] 21 Claims
 
1. A method of:
(a) reducing microbial load on a surface comprising applying a compound comprising a nitric oxide donor to a surface contaminated with a plurality of microbes;
wherein the nitric oxide donor generates nitric oxide and induces oxidative or nitrosative damage to microbial DNA and membrane structures, thereby reducing microbial load, and
wherein said plurality of microbes comprises two or more of the following: gram-positive bacteria, gram-negative bacteria, fungi, yeast, and viruses;
(b) treating a microbial infection comprising, contacting a surface contaminated with a plurality of microbes with a compound comprising a nitric oxide donor;
wherein the nitric oxide donor generates nitric oxide and induces damage to the membrane or DNA of the microbes, thereby reducing the number of viable microbes and treating the infection, and
wherein said plurality of microbes comprises one or more of viruses, gram positive bacteria, gram negative bacteria, drug resistant bacteria, molds, yeasts, fungi, and combinations thereof;
(c) reducing the viscoelasticity of a mucus layer, comprising contacting a surface comprising a mucus layer with a compound comprising a nitric oxide donor;
wherein the nitric oxide donor generates nitric oxide and
wherein the nitric oxide disrupts mucin-mucin interactions in the mucus layer, thereby decreasing mucus viscoelasticity;
or,
(d) delivering nitric oxide to a target site at an anti-microbial concentration for a period of at least 1 to 15 hours, comprising contacting a target site contaminated with a microbial load with a compound comprising a nitric oxide donor;
wherein the nitric oxide donor generates nitric oxide at a concentration sufficient to reduce the number of viable microbes at the target site;
wherein,
the compound in each of (a), (b), (c), and (d) is a functionalized alginate comprising one or more covalently modified monomers of Formula I

OG Complex Work Unit Chemistry
and optionally, one or more monomers of Formula II

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wherein,
R1 and R2 are each independently selected from the group consisting of hydrogen, C1-5 alkyl(C═O)—, and C1-5 alkyl;
R3 is hydrogen or C1-5 alkyl;
R4 is, in each instance, hydrogen or C1-5 alkyl;
Q is —(CRaRb)v—;
wherein Ra and Rb are independently hydrogen or C1-5 alkyl; and v is an integer from 2 to 6;
A is

OG Complex Work Unit Chemistry
wherein, L is S, O, or N; and
G, in each instance, is hydrogen, is taken together with L to form a nitric oxide donor, or is absent;
wherein the nitric oxide donor is selected from the group consisting of a diazeniumdiolate, a nitrosamine, a hydroxyl amine, a hydroxyurea, a nitrosothiol, a hydroxyl nitrosamine, and a combination thereof;
p is an integer from 1 to 10;
B is selected from the group consisting of hydrogen, —Y—Z, and C1-5 alkyl, wherein said C1-5 alkyl is optionally substituted with amino, hydroxyl, nitrile, CO2H, mono(C1-6)alkylamino-, di(C1-6)alkylamino-, —(CO)NRcRd, or —NRc(CO)Rd,
wherein Rc and Rd are each independently selected from the group consisting of hydrogen and C1-6 alkyl,
wherein Y has a structure of:

OG Complex Work Unit Chemistry
wherein Rp, Rq, Rs and Rt, in each instance, are independently, hydrogen or hydroxyl; and
k is an integer from 1 to 20; and
Z has a structure of:

OG Complex Work Unit Chemistry
wherein j, in each instance, is an integer from 1 to 100; and
wherein the functionalized alginate comprises at least one monomer of Formula I containing the nitric oxide donor.