INTRODUCTION:

Aminopyrimidine analogs have a great importance. Aminopyrimidine analogs can be used as chemotherapeutic agents for the treatment of diseases resulting from microorganisms as well as various metabolic disorders.

Miscellaneous biological activities:

Antidiabetic:

Pyrido [2,3-d]pyrimidine-2,4-diamine compounds shows PTP1B inhibitionN⁴-methyl-7-(2-phenoxy-6-triflouromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine(XXXa) shows good in-vitro inhibition of PTP1B, IC₅₀(μm) 0.17. {4-[2-(2-Amino-4-methylamino-pyrido [2,3-d]pyrimidin-7-yl)-3-trifluoromethyl-phenyl]-3,4-dihydro-2H-pyrazin-1-yl}-furan-2-yl-methanone (XXXb) shows IC50(μm) 0.30. PTP(protein tyrosine phosphatase) inhibitor can be used as therapeutic agent for the treatment of diabetes ⁵⁷.

Rheumatoid arthritis

Antiasthmatic

4-(amino-and aminoalkyl) cyclohexane-1-carboxamide derivatives shows antiasthamatic activity³⁶

Antiviral/ AntiHIV agents

Diuretic

XXXa XXXb

Compounds having substituted Aminopyrimidine

Various compounds having substituted aminopyrimidine moiety shows different activities

Antiviral/AntiHIV:

HIV virus infect human T₄ cells preferentially and thus disbalancing the immune system. The synthesized aminopyrimidines show activity against HIV 1 strain due to their antiretroviral properties.These compounds are useful against HIV infection. Some of these compounds(XXXI) shows IC50-0.0006and CC50-7.7⁵⁸.Arylaminopyrimidine derivatives(XXXII) shows remarkable HIV inhibition.IC50-0.0004,CC50-4.7⁵⁹

R2 = R3= R4 = H

XXXI

XXXII

150

Kinase inhibitor / modulator:

Rho proteins plays an important role in controlling different biological responses thus the Rho kinase inhibitors can be used for the treatment of cardiovascular diseases like hypertension, atherosclerosis, CNS disorder, inhibition of tumor cell growth and metastasis, intraocular pressure can also be regulated. Rho kinase biochemical assay shows that Pyrimidineamines are good rho kinase inhibitors⁶⁰.

Kinase inhibitor can be administered in combination with anticancer agents. Another use is to treat the side effect of radiation therapy such as antiemetic, radiation protectants, coadministration of these compound can be done along with tricyclic antidepressants, non tricyclic antidepressants, calcium antagonist, antihypertensives, antiarrhythmic drugs synthesized.4,6-diaminopyrimidines (XXXIII) shows IC50 -1.0 mm for EGFR kinase. Similarly phenylaminopyrimidine (XXXIVa, XXXIVb) compound shows IC50 value 38nm, 50mm for v-Abl and PDGFR respectively⁶¹.

Some urea derivatives like 2,6-di-morpholin-4-yl-pyrimidine-4-carboxylic acid {4-[3-(5-tert-butyl-4,5-dihydro-isoxazol-3-yl)-ureido]-phenyl}-amide and1-(5-tert-butyl-4,5-dihydro-isoxazol-3-yl)-3-[4-(2,6-diamino-pyrimidin-4-ylamino)-phenyl]-urea(XXXVa.XXXVb) shows kinase modulating properties. Kd values were determined for different compounds. Binding assay reveals that some compounds having very good affinity with Kd value <100 nm. Kd for molecule-Abl interaction, MKNK2 interaction, STK interaction were determined. In signal transduction pathway protein kinases play an important role, thus regulating cell differentiation, growth and cell death, protein kinases catalyze the phosphorylation of serine, threonine and tyrosine residue on proteins thus these compounds can treat or prevent conditions or diseases such as cardiovascular diseases, hematological malignancies and cancer⁶².

R₁= (CH₃)₃C,(CH₂)₂S,CF₃

R₂= H, (CH₂)₅S

R₃= , ,

XXXIII

XXXVa XXXVb

XXXIVa XXXIVb

Antimicrobial:

Some aminopyrimidines (XXXV) have been synthesized which inhibit DNA Polymerase111 ,thus, are useful against various microorganisms such as methicillin resistant S.aureus, methicillin resistant S.epidermidis, Bacillus subtilis etc. These compounds were tested for inhibition assay(range of activity is about 2-25µm),DNA Polymerase 111 inhibition whole-cell-based assay, MIC assay(range of activity-<0.5to 50μm),MOA assay(range of activity is between 1-25µm) [63]. DHFR inhibition in penicillin resistant Streptococcus pneumoniae and Staphylococcus aureus was shown by 5-(6-chromenylmethyl)-2,4-pyrimidinediamine derivatives (XXXVI) with IC50 values of 0.052M and 0.15M respectively [64]. Various indole derivatives(XXXVII)were prepared with replacing chromenyl moiety as antibacterial agents.They show the MIC value of 0.06μg/ml against Streptococcus pneumoniae [65].DNA polymerase III selectively inhibited by 6-(4-bromophenoxy)-N-4-(3-ethyl-4-methylcyclohexa-2,4-dienyl)-pyrimidine-2,4-diamine (XXXVIII) reported IC₅₀value 10 μM against DNA polymerase III against S.aureus.⁶⁶

Mycobacterial enoyl-ACP reductase was found to be inhibited by 2-(pyrazol-1-yl) pyrimidines (XXXIX) compounds⁶⁷.

Anticancer:

2,4-diamino-5-substituted-phenylazo-6-substituted aminopyrimidines have been synthesized and evaluated for their anticancer property against leukemia P388 compound 4-[2,4-diamino-6-(4-bromophenylamino)-pyrimidin-5-ylazo]-benzenesulfonic acid(XXXX) shows maximum activity⁶⁸.

XXXVIII XXXVII

R₁=alkyl, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl , dialkylsulfamoyl, phenylalkyl

R₂= H, halo, alkyl, alkanoyl, phenyl, phenylalkyl

R₃=H, alkyl

R₄= alkyl, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl,

heterocyclolalkyl, phenylalkyl

XXXIX

R₁=unsubstituted phenyl,heteroaryl

R₂=H,halo,alkyl

Other biological activities:

Cardiovascular:

For example minoxidil is 2,4-diamino-6-piperidinylpyrimidine-3-oxide(XXXXI).It has been found that pyrimidine sulphates are potent hypotensive.Minoxidil sulphate is more potent and has greater onset of activity than minoxidil [69].4-(amino and aminoalkyl)cyclohexane-1-carboxamide(XXXXII)[70] derivatives also shows antihypertensive and vasodilator activity.

As H₄ligand:

Histamine H4 receptor is G protein coupled receptor.H4 receptor expressed in major amount in eosinophils and mast cells beside other inflammatory cells. Thus can be targeted for various inflammatory disorders. Diseases which can be treated with H4 ligands include inflammatory bowel diseases, Crohn’s disease, dermatitis, psoriasis, rheumatoid arthritis, conjunctivitis, allergic rhinitis, asthama and bronchitis. Ki values were calculated for competition binding studies. Ki value having <500nm should be prefered. Some of the synthesized 2,4-diaminopyrimidines derivatives

N-4-isobutyl-6-(3-methylaminoazetidin-1-yl) pyrimidine-2,4-diamine,N-4-ethyl-6-(octahydropyrrolo[3,4-b]pyridin-6-yl)pyrimidine-2,4-diamine (XXXXIIIa, XXXXIIIb) shows the Ki value 14 and 30 [71] .

As H₄ receptor antagonist:

Histamine has a wide range of physiological effects. Various inflammatory actions of H4 receptor have been quoted especially calcium mobilisation, chemotaxis of murine mast cells and eosinophils, upregulation of adhesion molecules. Thus H-4 receptor antagonist can be used for treatment of many diseases and disorders such as acute respiratory distress syndrome, allergic rhinitis, allergic congestion, COPD, dermatological diseases like psoriasis and dermatitis. Some 2-aminopyrimidines derivatives (XXXXIV) have been synthesized. There screening was performed with Human H₄ GTPγS³⁵assay.

They show H₄receptor antagonism.(Ki /EC₅₀ value 75-250 nm).In HumanH₄R³ Histamine binding assay compound show the Ki /EC₅₀ value in between 200-450 nm[72]

Wnt signaling pathway modulator:

Wnt signaling pathway plays a role in gene regulation which are involved in various biological processes such as cell adhesion, proliferation and differentiation.wnt signaling thus provide useful tools for the study of embryogenesis and tissue hemostasis and regeneration. B-catenin / CTF transcriptional activity is dependent on wnt signaling and can be used for monitoring wnt signal pathway activity . EC50 values were measured when the signal inhibition is by 50%.EC50 values of some compounds XXXXVa, XXXXVb, XXXXVc were0.7,1.0,0.9,0.8µm⁷³.

XXXXI XXXXII

R=alkyl group

XXXXIIIa XXXXIIIb

XXXXIV XXXXVa

XXXXVb XXXXVc

XXXXVd

CONCLUSION:

It is found that during last decade a number aminopyrimidine containing drugs have been synthesized with broad spectrum of biological activities, thus, the aminopyrimidine moiety can be a future candidate for the synthesis of drugs, especially as antiinfectives and antitumor agents.

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