Recent Developments and Biological Activities of 2-Aminothiazole Derivatives

Aminothiazole nuclei and their various derivatives have been long used as precursors for the synthesis of biologically active molecules. As a typical heterocyclic amine, 2-aminothiazole is a cornerstone for the synthesis of many compounds, including sulfur drugs, biocides, fungicides, various types of dyes for synthetic fibers and chemical reaction accelerators and as intermediates in the synthesis of antibiotics, where a large number of 2-aminothiazoles have been substituted with different groups for various pharmaceutical purposes, besides their activity as corrosion inhibitors for mild steel protection as well. The synthetic utility of 2-amino-4-substituted-thiazoles, their reactions and biological activities have been surveyed and are presented in this review.


Introduction
2][3] As a typical heterocyclic amine, 2-aminothiazole is the starting point for the synthesis of many compounds, including sulfur drugs, biocides, fungicides, dyes and chemical reaction accelerators and as intermediates in the synthesis of antibiotics, where a large number of 2-aminothiazoles have been substituted with different groups for pharmaceutical purposes, [4][5][6] and are also used in the syntheses of various types of dyes for synthetic fibers, [7][8][9][10][11][12][13][14][15] beside their activity as corrosion inhibitors for mild steel protection, 16,17 corrosion inhibitors for copper 18 and as an ionophore in the construction of a lutetium(III)-selective membrane sensor. 19These derivatives continue to attract the attention of biologists because of their widespread use in the treatment of the biological systems.For instance, many papers have been published on the use of these compounds exhibiting antimicrobial, [20][21][22] antifungal and anti-inflammatory activity, 23 anesthetic activity, 4,24 as antiviral drugs, 6 anti-leukemic agents, 25 antiproliferatives (cytostatic and cytotoxic) with activity against a panel of cell lines (HeLa, L929, HT-29 and T47D), 26 as active agents against some enzymes involved in eicosanoid metabolism (5-, 12-, 15-lipoxygenase (LO), cyclooxygenase-1 and -2 (COX-1 and COX-2)), 27 inhibitors anti-TCR antibody induced IL-2 production in mice in vivo and reduced lung inflammation in a mouse model of ovalbumin induced allergy/asthma, 28 inhibitors for Mycobacterium tuberculosis (Mtb, H37Rv and MS, GyrB), 29,30 as vascular adhesion protein-1 inhibitors (VAP-1), 31,32 inhibitors of Cdc7 kinase activity in cancer cells, 33 inhibitors of nerve growth factor receptor TrkA, 34 inhibitors of p38α mitogen-activated protein kinase (p38α MAPK). 35They can also bind to CT-DNA by the intercalative and electrostatic binding mode. 36A clubbed triazolyl thiazole series of cdk5/p25 inhibitors were reported as potentially useful compounds for the possible treatments for Alzheimer's disease. 37Due to its enormous industrial and biological importance, the studies of tautomeric equilibriums of 2-aminothiazole and its derivatives have been considered as a hot topic for the scientists. 380][41][42][43] Several spectroscopic investigations, e.g.infrared (IR), ultraviolet (UV), density functional theoretical calculations (DFT), Raman spectra (RS),

1. 1. Using Halogen
Ketones of the type 1 react directly with one mol of halogen and two mols of thiourea to give 2-amino halogenated derivatives of the 4-substituted-1,3-thiazole nucleus 2 in excellent yield. 50,51

From Various Acetophenone Derivatives
Diazoacetophenone 15 was reacted with thiourea to furnish 2-amino-4-phenyl thiazole 3. The reaction has been affected either by heating an intimate mixture of the reactants on the steam bath, or by refluxing an ethanol solution of the reaction components. 71omoacetophenoneoxime 16 and 2-bromo-1-phenylethylidenemalononitrile 17 were reacted with thiourea to give 2-amino-4-phenyl thiazole 3. The ring closure has been accompanied by the elimination of hydroxylamine 72 or malononitrile, 73 respectively.Cyclocondensation of bromoacetophenone with 2-furoyl thioamide derivatives in diluted acetic acid, gave Khalifa M. E.: Recent Developments and Biological Activities ... a series of 2-amino-5-benzoyl-4-(2-furyl)thiazoles 18.The synthesized derivatives were screened for in vitro anti-tubercular activities against Mycobacterium tuberculosis H37Rv using the Microplate Alamar Blue Assay (MABA), for antibacterial activities with agar dilution method against clinical Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae and penicilin-resistant Streptococcus pneumonia, 74 and exhibited excellent affinity for A 2A receptor as well. 75action of haloketophenoxybenzene derivative 19 with thiourea gave the 2-amino-5-[4-(4'-nitrophenoxy) phenyl]thiazole (APPT) 20.Additionally, a series of novel polyimides were prepared by polycondensation of APPT with various aromatic dianhydrides via one-step process and multi heterocyclic Schiff bases were also prepared as anticancer agents against human breast, colon and prostate cell lines.Also, the resulting polyimides have high Tg values, excellent thermal and thermo-oxidative stability, as well as good solubility in organic solvents.[78][79] The reaction of bromomethoxyacetophenone derivatives 19 with potassium thiocyanate in dry benzene afforded 2-thiocyanoacetophenones 20, which underwent cyclization in the presence of alumina-supported ammonium acetate to give 2-aminothiazole analogues 21 as described by Kodomari et al.The synthesized compounds exhibited potent and selective human adenosine A3 receptor antagonists. 80

6. From Imine Derivatives
Halo-methyl ketimines 32 (X = Br, Cl) have been condensed with thiourea in methanol to afford 2-amino-4-substituted thiazoles 3, whereas the N-isopropyl moiety had been lost during the condensation of the halo-ketimines. 85

7. From Nitriles
A series of 2-(2,4-disubstituted-thiazole-5-yl)-3-aryl-3H-quinazoline-4-one derivatives 34 were designed and synthesized by reaction of active α-halo derivative 33 of substituted quinazoline with acetonitrile, where the products exhibited selective and dual inhibition against NF-KB, AP-1 mediated transcriptional activation and significant efficiency in the in vivo models of inflammation. 86amines of the type 35 were reacted with elementary sulphur and cyanamide at room temperature without catalyst to give the corresponding 2-amino-4-substituted thiazoles 3. 87 The condensation of thiourea and halogeno-nitriles to form salts of 2,4-diaminothiazole is a general reaction, which is, however, limited by the inactivity of the halogens in some substituted nitriles, e.g.chloroacetonitrile 36 reacts with thiourea in cold ethanol to give the halogenated salt of 2-halogenated amino-4-substitued thiazole derivative 2. 88

8. From Alkynes
The formation of 2-amino-4-substituted thiazoles 3 (R = C 4 H 9 , C 6 H 5 ) in a single reaction step from alkynyl(phenyl) iodoniummesylates 37 and thiourea can be rationalized mechanistically by a thiophilic attack of the hypervalent iodine atom on the sulphur atom of the thiocarbonyl group. 89

9. From Esters
e coumarin carboxamide derivatives 40 have been prepared from the corresponding coumarincarboxylic acid and 2-amino-4-substituted thiazoles 3. The compounds have been tested for anti-fungal and antibacterial activity.91 Condensation reaction of 2-aminothiazole derivatives with various types of carbonyl compounds afforded different thiazols, where 2-amino-4,5-disubstituted thiazoles 3 (R = substituted phenyl; R 1 = H, CH 3 ) condensed with 4-methoxy-4-oxobutanoic acid, 2-chloroacetyl chloride followed by mercaptoacetic acid and/or 4-chlorobutanoyl chloride to form the thiazole based derivatives 41, 42 and 43, respectively.The products were considered as lipid carriers having a significant role in the metabolic syndrome in A-FABP/ap2-deficient mice, including type 2 diabetes, atherosclerosis and anticonvulsant gradients.92,93 The 2-amino-4-substituted thiazole tetrazole derivatives 44 have been prepared by the treatment of 2-amino-4-substituted thiazoles 3 with a suspension of dipotassium-1H-tetrazole-5-carboxylate in acetonitrile containing pyridine.Compounds 44 exhibited inhibition of anti-passive cutaneous anaphylaxis in rats.94 Imidazo[2,1-b]thiazoles 45 and 46 were synthesized through the reaction of 2-aminothiazoles 3 with different acid derivatives.The study of the synthesized compounds indicated a high degree of selectivity for inhibition of RSK2 compared to a spectrum of other related kinases, resulting in selective inhibition of the MCF-7 breast tumor cell line, as well as selective inhibition of the biomarker GSK3. 95

1. Reaction with Aliphatic and Aromatic Amines
A novel series of 2-acetamido and 2-propanamido derivatives of 4-substituted thiazoles 110 was designed and synthesized by the reaction of 2-amino-4-substituted thiazoles 3 with chloroacetyl chloride derivatives, followed by the reaction with secondary aromatic and/or aliphatic amines.The synthesized compounds were subjected to NCI in vitro assessment for their antitumor activity and remarkable GI values of 75.5, 69.3, 96.2 and 92.7% to the Leukemia CCRF-CEM cell line were determined. 164
Coupling of the diazotized 2-amino-2,4-disubstituted-thiazoles 123 (R = CH 3 ; R 1 = COCH 3 ) with various N-alkyl derivatives of aniline afforded the corresponding 2-azoaryl-2,4-disubstituted-thiazoles 124.The products were applied as disperse dyes and their dyeing performance has been assessed on cellulose triacetate fabric.The dyed fabrics show good light fastness, very good rubbing, perspiration, washing fastness and excellent sublimation fastness.These dyes have been found to give bright yellow to maroon color shade with very good depth and levelness on fabric,173 while 124 (R 1 = R 2 = Cl; R 3 = C 2 H 4 OH; R 4 = H) dyed polyester fiber with superior depth and levelness and fair to very good light fastness, very good to excellent washing and rubbing fastness properties.174Azo coupling of 5-formylaminothiazole derivative 3 (R 1 = OCH 3 ; R 2 = CHO) as the diazo component and N,N-diethylaniline afforded the formyl aminothiazole dye 125.The synthesized asymmetrical 2D charge transfer chromophores showed good nonlinear optical response and good thermal stability as well.