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ISOTHIAZOLINONE

CAS: 1003-07-2
European Community (EC) Number: 696-206-9

IUPAC Name: 1,2-thiazol-3-one
Molecular Formula: C3H3NOS
Molecular Weight: 101.13

Isothiazolinone (sometimes isothiazolone) is an organic compound with the formula (CH)2SN(H)CO.
A white solid, it is structurally related to isothiazole.
Isothiazolinone itself is of limited interest, but several of its derivatives are widely used preservatives and antimicrobials.

The importance of isothiazole and of compounds containing the isothiazole nucleus has been growing over the last few years.
Isothiazolinones are used in cosmetic and as chemical additives for occupational and industrial usage due to their bacteriostatic and fungiostatic activity.

Organic compounds containing five-membered heterocyclic rings play an important role in many industrial sectors.
Among them, isothiazole and its derivatives have found applications in different fields since they present useful biological properties, such as antimicrobial, antibacterial, antifungal, antiviral, anticancer, and anti-inflammatory activities.
Furthermore, isothiazoles have been described to act as inhibitors of proteases for the treatment of anxiety and depression, as inhibitors of aldose reductase, and as 5-hydroxytryptamine receptor antagonists.
Chemically, isothiazole (1,2-thiazole) is a five-membered heteroaromatic that is considered to be derived from thiophene, in which the second position is occupied by a nitrogen atom.

The noticeable biological effects observed for isothiazole-containing compounds have generated an enormous interest on this scaffold for drug discovery and development programs, which resulted in a steady increase in the number of related patent applications as well as in the successful introduction of isothiazole-based derivatives to the market.
Among them, the most extensively used for industrial applications and reactive intermediates, for the synthesis of various organic substances including pharmaceuticals and agrochemicals, are those based on isothiazolin-3-one (isothiazolinone).

Isothiazol-3-ones are known for their remarkable antifungal and antibacterial properties, being extensively used as biocides in a variety of industrial water treatment applications for the control of microbial growth and biofouling.
They have also been recommended as preservatives to prevent fungal growth in a wide range of manufactured goods, such as emulsion paints, wood varnishes, adhesives, and natural and artificial leather.
The isothiazolinones most commonly found in commercial applications, alone or in combination, are methylisothiazolinone (MI), methylchloroisothiazolinone (MCI), benzisothiazolinone (BIT), octylisothiazolione (OIT), and dichlorocthylisothiazolinone (DCOIT).
Methylisothiazolinone is commonly used in wastewater treatment processes, cosmetics, paints, and detergents, and in combination with MCI (in proportions of 3:1) as an active ingredient of a commercial biocide.

The antimicrobial profile of isothiazolinones makes them highly efficient biocides, even at low concentrations.

Isothiazolinones are preservatives commonly found in many consumer products in the U.S. and in other countries, including cleaning products, cosmetics, and water-based paint.
Isothiazolinones are a group of heterocyclic sulphur-containing compounds.
There are several members of the isothiazolinone family, including methylisothiazolinone (MI), methylchloroisothiazolinone (MCI), benzisothiazolinone (BIT), and octylisothiazolinone (OIT).
Isothiazolinones contain an activated N-S bond that reacts with cellular nucleophiles, which is the mechanism of their biocidal activity.
MCI has an additional chlorine, which increases its microbial efficacy.
These preservatives have a low molecular weight, and can penetrate the skin.
Their reactivity with cellular nucleophiles, which provides biocidal activity, also allows them to react with cellular proteins, causing a sensitization reaction.

There are many consumer products that contain isothiazolinones, including products that are intended to contact or remain on skin, such as cosmetics, hair care products, soaps/cleansers, sunscreens, and cleaning wipes.
Isothiazolinones are commonly used in combination in formulations because they vary in stability and efficacy.
For example, MCI/MI has a broad spectrum efficacy against bacteria, algae, and fungi.
BIT has a narrower range of targets but is useful for longer term preservation.
Therefore, many products contain combinations of isothiazolinones, such as MI and BIT, in order to preserve products.

Isothiazolinone is an antimicrobial preservative that is commonly used to control bacteria, fungi, and algae.
Isothiazolinone is most commonly applied in water containing solutions, as these solutions are a breeding ground for bacteria.
There are a number of different products on the market today that use Isothiazolinone like sunscreen, hand sanitizer, shampoo, cosmetics, lotions, and many more.
The purpose of including Isothiazolinone in these products is to inhibit microbial activity that could potentially spoil the product before its expected expiration date.

Synthesis
Compared to many other simple heterocycles, the discovery of isothiazolinone is fairly recent, with reports first appearing in the 1960s.

Isothiazolinones can be prepared on an industrial scale by the ring-closure of 3-mercaptopropanamides.
These in turn are produced from acrylic acid via the 3-mercaptopropionic acid:

Ring-closure of the thiol-amide is typically effected by chlorination or oxidation of the 3-sulfanylpropanamide to the corresponding disulfide.
Many other routes have been developed, including addition of thiocyanate to propargyl amides.

Mechanism of action
The antimicrobial activity of isothiazolinones is attributed to their ability to inhibit life-sustaining enzymes, specifically those enzymes with thiols at their active sites.
It is established that isothiazolinones form mixed disulfides upon treatment with such species.

Isothiazolinones (CMIT/MIT) is composed of 5-chloro-2-methyl-4-thiazoline-3-ketone (CMI) and 2-methyl-4-thiazoline-3-ketone (MI).
The bactericidal effect of Isothiazolinones (CMIT/MIT) is carried out through breaking the bond between bacteria and algae protein.
When contacted with microbes, Isothiazolinones (CMIT/MIT) can quickly inhibit their growth, thus leading to death of these microbes.
Isothiazolinones (CMIT/MIT) has strong inhibition and biocidal effects on ordinary bacteria, fungi and alga, and has many advantages such as high biocidal efficiency, good degradation, no residual, safety in operation, good compatibleness, good stabilization, low cost in operation.

Isothiazolinones (CMIT/MIT) can mix with chlorine and most cation, anion, and non-ionic surfactants.
When used at high dosage, its biosludge stripping effect is excellent.

Isothiazolinones (CMIT/MIT) is a kind of fungicidal with properties of broad spectrum, high efficiency, low toxicity and non-oxidative, it is the ideal biocidal in industrial circulating cool water system and in wastewater treatment in oilfield, papermaking, pesticide, cutting oil, leather, detergent and cosmetics etc..

Applications
The principal isothiazolones are:

Methylisothiazolinone (MIT, MI)
Chloromethylisothiazolinone (CMIT, CMI, MCI)
Benzisothiazolinone (BIT)
Octylisothiazolinone (OIT, OI)
Dichlorooctylisothiazolinone (DCOIT, DCOI)
Butylbenzisothiazolinone (BBIT)
These compounds all exhibit antimicrobial properties.
They are used to control bacteria, fungi, and algae in cooling water systems, fuel storage tanks, pulp and paper mill water systems, oil extraction systems, wood preservation, and some paints.
They are antifouling agents.
They are frequently used in shampoos and other hair care products.

Chloromethylisothiazolinone (CMIT) and 2-methyl-4-isothiazolin-3-one (methylisothiazolinone or MIT) are popular derivatives.
A 3:1 mixture of CMIT:MIT is sold as Kathon.
Kathon is supplied as a concentrated stock solution containing from 1.5 to 15% of CMIT/MIT.
For applications the recommended use level is from 6 ppm to 75 ppm active isothiazolones.

4,5-Dichloro-2-n-octyl-4-isothiazolino-3-one (DCOI or Sea-Nine 211) is used especially as an antifouling agent, i.e. paint for ship hulls to prevent the formation of barnacles, etc.

SYNONYMS:

isothiazolone
1,2-thiazole 1-oxide
140651-38-3
Isothiazole 1-oxide
SCHEMBL21754
DTXSID40577741
1H-1lambda~4~,2-Thiazol-1-one
1003-07-2
Isothiazol-3(2H)-one
3(2H)-Isothiazolone
3-Isothiazolone
Isothiazol-3-one
isothiazol-3-ol
1,2-thiazol-3-one
ISOTHIAZOLINONE
3-Hydroxyisothiazole
4-isothiazolin-3-one
1,2-thiazol-3-ol
3-Oxo-2,3-dihydroisothiazole
THIAZOL-3-ONE
E57JT172V7
NSC93489
MFCD09834764
NSC-93489
1,2-Thiazol-3(2H)-one
NSC 93489
Isothiazol-3(2H);-one
NCIOpen2_001597
SCHEMBL19431
isothiazol-3-ol, AldrichCPR
UNII-E57JT172V7
CHEMBL1974422
DTXSID9074935
2,3-dihydro-1,2-thiazol-3-one
ZINC1604240
PT-490
AKOS006345440
AKOS024046921
AT11769
GT-2060
PS-9316
A-01
AC-25099
BL007960
NCI60_042085
SY045488
DB-014833
3(2H)-Isothiazolone;Isothiazol-3(2H)-one
CS-0005502
FT-0742113
EN300-108635
003I072
858I671
A850091
Q409007
F2167-8909
Z1741980421
3-(2-chlorophenyl)-5-(3-chloropropyl)-1,2,4-oxadiazole