a review: 3, 4-dihydropyrimidines thione their chemistry and pharmacological potentials
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Int. J. Pharm. Res. Sci.,2013,01(1),1-6. ISSN:2348 –0882
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A Review: 3, 4--Dihydropyrimidines Thione Their Chemistry and Pharmacological Potentials
Kadam NR*S.L.S.A.D.Pharmacy College, Hokarna Campus, Mukhed, Maharashtra, India.
============================================================================AbstractPyrimidine is a six membered heterocyclic ringhaving two nitrogen (N) atoms in their ring.Pyrimidine having molecular formula of C4H4N2
and molecular weight = 80 Dalton.Dihydropyrimidines are the compounds which areobtained by cyclocondensation reaction whichhaving different products. The dihydropyrimidinesynthetic product has different medicinal uses suchas Antihypertensive, Antibacterial, Antifungal andantioxidant property. The present review focuseson 3, 4--Dihydropyrimidines Thione TheirChemistry and Pharmacological Potentials.IntroductionPyrimidine is a six membered heterocyclic ringhaving two nitrogen (N) atoms in their ring.Pyrimidine having molecular formula of C4H4N2
and molecular weight = 80 Dalton.Physical Properties and Structure: Pyrimidineis a colourless compound, having melting point22.50C and boiling point 1240C. Its dimensionshave been determined by an X-ray diffractionstudy of a crystal at -20C and closely look likethose of pyridine (six membered hetrocyclics withone nitrogen atom in their ring).
N
NPyrimidine is best considered as a resonancehybrid to which the uncharged equivalent kekulestructures 1 and 2 and the charged structures 3-8contribute. The self-consistent pai electondensities, designed for ground state of pyrimidine,are 0.776, 0.825, and 1.103 for positions 2, 4, and5, respectively.====================================Corresponding Author: Kadam NREmail id: [email protected]: 07.11.2013Revised: 08.12.2013Accepted: 10.12.2013
Chemical properties of pyrimidine and itsderivatives:Pyrimidines can be considered best as derivativesof pyridine and, to a lesser extent, as cyclicamidines. Pyrimidine, which accepts two protonsunder extremely acidic conditions (pKa1 1.3 pKa26.9), is much weaker base than pyridine (pKa5.23), imidazole (pKa 7.2), or amidines in general.This is because, different imidazole and amidines,the addition of a proton does not increase thepossibilities for resonance and hence theresonance energy. It is a unpredictably weakerbase than pyridazine (pKa 2.33). Only one of thenitrogen atoms of the pyrimidine is alkylated byalkylating agents, such as methyl sulphate, but themuch more potent agenttriethyloxoniumborofluoride alkylates bothnitrogen atoms to give a ring bearing two positivecharges.[1]
Electrophilic Reactions: From the considerationof the charged structures contributing to theresonance hybrids represents pyrimidine andpyridine, and the pair electron densities, it isobvious that the position 5 of pyrimidine whichshould match up to position 3 of pyridine and bethe most susceptible in the ring to electrophilicattack. Pyrimidine hydrochloride is brominated atposition 5, but no other electrophilic substitutionof pyrimidine itself has been claimed. If activatinggroups, such as hydroxyl or 2 õother positions in the molecule, electrophilicsubstitution (nitration, nitrosation, diazocoupling)usually occurs, but only at position 5. [2]
Int. J. Pharm. Res. Sci.,2013,01(1),1-6. ISSN:2348 –0882
2
BrN Br2 N
nitrobenzeneN N
H3C
H3C
O
NNH
N NO
Nucleophilic Reactions: Positions 2, 4, and 6 ofpyrimidine formally correspond to those of 2 or 4of pyridine and, in the few cases investigated, are
HOH2C
CH 2 CH 2 OH(CHOH) 3
S
+Nattacked by nucleophilic reagents such assodamide (NaNH2) and phenyl magnesiumbromide (PhMgbr) However; pyrimidine itself isdecomposed by hot aqueous alkali. Pyrimidine is
H 3 C
+
H N N
N H 2
attacked at the 2- and 4-positions by the 4nitrophenyl radical. [2]
H 3 C
RIBOFLAVIN
N phLi
H Ph
NH
Ph
(O) N
THIAMINEPyrimidine nucleus is also present in barbituricacid and its several derivatives e.g. Veranal)
[5]
EtherN N
KMnO4
Acetone N
which are used as hypnotics.O
Biological Importance of Pyrimidine: Inmedicinal chemistry pyrimidine derivatives havebeen very well known for their therapeuticapplications. The presence of a pyrimidine base inthymine, cytosine and uracil, which are theessential building blocks of nucleic acids, DNAand RNA is one of the possible reasons for theiractivities.[3]
NH
HO N OH
OH5C2
H5C2 NH
H O N OO H NH2N
O N H
H N HNC H 3
O O N
BARBITURIC ACIDHN VERANAL
In addition to this, pyrimidine nucleus is alsofound in alloxan, which is well-known for itsO
THYMINE CYTOSINE diabetogenic action in a number of animals.O
[6]
URACILVitamins are essential for body. Pyrimidine ring isfound in vitamins similar to riboflavin, thiamineand folic acid.[4]
ONH
O N OH
ALLOXANDihydropyrimidines - IntroductionThe first synthesis of dihydropyrimidines wasreported by Biginelli7 in 1893; however, thesynthetic potential of this heterocyclic synthesisremained new for fairly some time. In the 1970’sinterest steadily increased, and the scope of theoriginal cyclocondensation reaction was graduallyunlimited by variation of all the building blocks,allowing access to a large number of
Int. J. Pharm. Res. Sci.,2013,01(1),1-6. ISSN:2348 –0882
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multifunctionalized dihydropyrimidines of varioustypes. Since the late 1980’s, a tremendousincrease in activity has again occurred, as evidentby the growing number of publications andpatents on the subject. This is mainly due to thefact that the multifunctionalizeddihydropyrimidine scaffold (“Biginelli
by only 40% with IC50s ranging from 100 to 300mM.[10]
-O Ar
H 5C 2 NH
compounds”) represents a heterocyclic system ofamazing pharmacological efficiency. Since then
H3C N O
C 4H 9Brseveral reviews on synthesis and chemicalproperties of pyrimidinones have beenpublished.The search for new and efficientmethods for the synthesis of pure compounds hasbeen an active area of research in organicsynthesis. From a modern point of view, Biginelliprocedure is obviously very attractive forcombinatorial chemistry and has been not oftenused for parallel synthesis, a new avenue could beconnected with an elaboration of catalyticprocedures.[7]In 1893, P. Bigenelli reported on theacid catalyzed cyclo-condensation reaction ofethyl acetoacetate, benzaldehyde, and urea. Thereaction was carried out by simply heating amixture of the three components dissolved inethanol with a catalytic amount of hydrochloricacid at reflux temperature. The product of thisnovel one-pot, three components synthesis thatprecipitated on cooling of the reaction mixturewas identified as 3,4-dihydropyrimidin-2(1H)-oneand this reaction is known as “Biginelli reaction”,or “Biginelli Condensation”, or as “Biginellidihydropyrimidine synthesis”. Since then anumber of improved variants employing newreagents, catalyst, methodologies and techniquehave developed till today.[8’9]
A. Dihydropyrimidines as calcium channelchannel blockers and antihypertensive
Kamaljit et al : were synthesized 3,4-dihydropyrimidine-2(1H)-ones under solvent-less,mild phase transfer catalytic (PTC) conditionswith tetrabutylammonium hydrogen sulfate and50% aqueous NaOH as the catalyst and base andscreened for calcium channel blocking activitybased on their ability to relax a membranedepolarization induced contraction of vascularsmooth muscle. The calcium channel blockerswere compared against nifedipine for their abilityto relax a membrane depolarization inducedcontraction. All synthesized compound weremaximally relaxed the KCl-induced contractions
Hiren et al : Were synthesize and in-vitroscreening of 3, 4-dihydropyrimidin2 (1H)-onederivatives for antihypertensive and calciumchannel blocking activity. Nifedipine was used asstandard reference drug for screening of antihypertensive and calcium channel blocker. amongall the eight synthesized compounds Compound6c was found to have better antihypertensiveactivity and compound 6f found to have bettercalcium channel blocker activity.[11]
R
C H 3
H N R 1
O NH
R= H, Cl R1= OC2H5, N (C2H5)2, N (CH3)2
Patil et al: were synthesize dihydropyrimidinonesin a three step reaction in presence of hydrazinehydrate, pyridine as intermediate by usingMicrowave synthesis .and screened forantihypertensive activity by non-invasive tail-cuff,and evaluated by carotid artery cannulationmethod for determining the diastolic bloodpressure. Hypertension was induced by DOCA-salt. Test compounds 1-8 exerted comparativeanti-hypertensive activity at 10 mg/kg dose levelcompared to nifedipine. Compounds 2, 4 and 8showed excellent results on evaluation by directmethod. Also Anti-inflammatory activity wascarried out by Carrageenan induced rat-pawoedema method. Test compounds 3, 4 and 7exerted moderate to comparative anti-inflammatory activity at the 100 mg/kg dose levelcompared to indomethacin.[12]
Int. J. Pharm. Res. Sci.,2013,01(1),1-6. ISSN:2348 –0882
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compounds are significantly active. Allcompounds have been screened for their
O Ar-
NHSO2 NH NH
thiones have been prepared by Mannich reactionwith seven different heterocyclic secondary aminocompounds and formaldehyde. In this reactionfour different derivatives of 3,4-
CH3
H3C N XH
dihydropyrimidines-2(1H) thiones have been usedas hydrogen active compounds. These precursorshave been derived by Biginelli reaction of fouraromatic aldehydes, namely benzaldehyde,salicylaldehyde, anisaldehyde, and vanillin ,
B. Dihydropyrimidines as antibacterialand antifungal evaluation
Okram et a l : synthesized dihydropyrimidinonesusing Copper (II) chloride in the absence of anysolvent and in vitro evaluate of the antifungalactivities against the radial growth of three fungalspecies viz., Trichoderma hammatumTrichodermakoningii and Aspergillus niger. Among all sixsynthesized compounds 4a, 4c, 4e shows highestgrowth inhibition. [13]
respectively with ethylacetoacetate and thiourea.All compounds are screened for in vitroantimicrobial activity against E coli and B.subtilis.and. antifungal activity against A.niger and C.Albicans. All compounds shows promisingantimicrobial activity against both bacterial andfungal microorganisms. [15]
R2
R1
OO R1 H
H5C2 NHH5C2O NH
H3C N SHH3C N X
HX= O, S R1= C6H5, 2-HOC6H4, 4-Me2NC6H4
Mohammad et al : were synthesizedDihydropyrimidinones and their thioanalogue bythree component condensation of Urea/thioureaethylacetoacetate and substituted aldehydes.Comparison shows that all the synthesized
antifungal activity against A. niger and C.Albicans using agar well diffusion method againstciclopiroxolamine. . From comparative activitystudy, it noticed that thione compounds showed
R1= H, OMe R2= H, OMe, oJayakumar et al: were synthesize substituted 3,4-dihydropyrimidin-2(1H)-ones (DHP) bycyclocondensation reaction between 3,4-dimethoxybenzaldehyde ( veratraldehyde), activemethylene compounds (acetyl acetone oracetoacetic ester) and urea / thiourea in presenceof CuCl2.2H2O and HCl by grindstone solventfree and ecofriendly technique. These synthesizedderivatives have been tested for antibacterialactivity against Micrococcus luteus , Escherichiacoli & Pseudomonas aeruginosa and for antifungalactivity against Aspergillus niger, Candida
[16]
more activity than pyrimidinone compounds. [14]
R 2
albicans & Candida kefyr .OCH 3
OCH 3R 1
O C H 3O
H N O
X N C H 3H
R N H
H 3 C N ZH
R1= H, No2 R2=OMe, H, Cl X=O, SShah et al : were synthesized Four series of N-Mannich base of 3,4-dihydropyrimidines 2(1H)
R= CH3, C2H5 Z= O ,S
C. Dihydropyrimidines as Antioxidantactivity
Int. J. Pharm. Res. Sci.,2013,01(1),1-6. ISSN:2348 –0882
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Nidhi G. et al : were synthesized 3,4-Dihydropyrimidin-2(1H)-one derivatives byOrganocatalysed microwave assisted synthesisusing oxalic acid as a new, efficient, andenvironmentally benign catalyst. Antioxidantproperties of synthesized compounds wereevaluated by three methods, viz., radicalscavenging effect on 2,2-diphenyl-1-picrylhydrazyl radicals, reducing power and Fe2Chelating activities. Amongst the 12 synthesizedcompounds, four were found to have significantantioxidant activity. [17]
;R 1
O
RO N H
Me NH
R= C2H5, CH3 R1= 4-NO2, 3-NO2, 4-OH
References:1. Anuradha Verma, Laxmikant Sahu,
Neelam Chaudhari, Tanushree Dutta,Dhansay Dewangan &D.K.Tripathi:Review: Pyrimidine Their Chemistry andPharmacological Potential. Asian Journalof Biochemical and PharmaceuticalResearch2012; Issue 1 (Vol. 2) ISSN:2231-2560.
2. Ahluwalia and Madhuri Goyal. Text Bookof Organic chemistry. ISt.ed: (2001); 777-717.
3. Raghav Mishra and Isha Tomar:Pyrimidine: The Molecule Of DiverseBiological and medicinal importance;IJPSR (2011), Vol. 2, Issue 4.
4. Cox RA; Quart. Rev.1968; 22; 499.5. Jain MK, Sharnevas SC; Organic
Chem.2008; 3; 997-999.6. . Eussell JA; Annu. Rev. Biochem.1945;
14; 309.7. I.T.Phucho, A.Salaya: Recent Progress In
The Chemistry Of dihydropyrimidinones;,Rasayan Journal of .chemistry(2009),Vol.2, No.3 662-676.
8. P. Biginelli, Chem Ber1891; 24: 1317. (b)P. Biginelli, Chem Ber1891; 24: 2962
9. Biginelli, Gazz. Chim. Ital. 1889; l 19:212. (b) P. Biginelli, Gazz. Chim. Ital.1893; 23: 360.
10. Kamaljit Singh, Divya Arora, ElizabethPoremsky, Jazmyne Lowery, Robert S.Moreland: N1-Alkylated 3,4-dihydropyrimidine-2(1H)-ones:Convenient one-pot selective synthesis andevaluation of their calcium channelblocking activity, European Journal ofMedicinal Chemistry (2009); 44: 1997–2001;
11. Hiren M. Marvaniya, Palak K. Parikh andDhrubo Jyoti Sen: Synthesis and in-vitroscreening of 3, 4- dihydropyrimidin-2(1H)-one derivatives for antihypertensiveand calcium channel blocking activity.Journal of Applied PharmaceuticalScience2011; 01 (05): 109-113.
12. P. A. Patil, R. P. Bhole, R. V. Chikhale,K. P. Bhusari: Synthesis of 3,4-Dihydropyrimidine-2(1H)-one Derivativesusing Microwave for their Biologicalscreening. International Journal ofChemTech Research 2009;Vol.1: No.2, :373-384 ,
13. Okram Mukherjee Singh a, SarangthemJoychandra Singh, Mutum Babita Devi ,Laitonjam Nalini Devi, NameirakpamIrabanta Singh, Sang-Gyeong Lee:Synthesis and in vitro evaluation of theantifungal activities ofdihydropyrimidinones. Bioorganic &Medicinal Chemistry Letters 2008; 18:6462–6467.
14. Mohammad Aslam and Shaifali Verma:Biological activity of newly synthesizedsubstituted Dihydropyrimidinones andThione. International Journal ofChemTech Research2012; Vol.4, No.1:109-111.
15. TB Shah, A Gupta, M R Patel, V CChaudhari, H Patel &V C Patel: Synthesisand in vitro study of biological activity ofheterocyclic N-Mannich bases of 3,4-dihydropyrimidines -2(1H)thione. Indianjournal of chemistry2010; Vol.49B:578-586.
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16. S. Jayakumar and T. K. Shabeer:Multicomponent Biginelli Synthesis of 3,4-dihydropyrimidin-2(1H)-ones bygrindstone technique and evaluation oftheir biological properties. Journal ofChemical and PharmaceuticalResearch2011; 3(6):1089-1096.
17. Nidhi Gangwar, Virendra Kumar Kasana:3, 4-Dihydropyrimidin-2(1H)-one
derivative: Organocatalysed microwaveassisted synthesis and evaluation of theirantioxidant activity. Medicinal ChemistryResearch 2012; DOI 10.1007/s00044-012-9987.
.