This document reviews 3,4-dihydropyrimidines thione, their chemistry and pharmacological potentials. It begins with background on pyrimidine structures and properties. It then discusses the chemical properties of pyrimidines and derivatives, including electrophilic and nucleophilic reactions. Biological importance is explained by pyrimidine's presence in nucleic acids, vitamins, and other biologically active compounds. Dihydropyrimidines are introduced as compounds obtained from cyclocondensation reactions. Several studies evaluating dihydropyrimidines as calcium channel blockers, antihypertensives, antibacterials, antifungals, and antioxidants are summarized.

1. Int. J. Pharm. Res. Sci.,2013,01(1),1-6.
ISSN:2348 –0882
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.
============================================================================
Abstract
Pyrimidine is a six membered heterocyclic ring
Chemical properties of pyrimidine and its
having two nitrogen (N) atoms in their ring.
derivatives:
Pyrimidine having molecular formula of C4H4N2
Pyrimidines can be considered best as derivatives
of pyridine and, to a lesser extent, as cyclic
and
molecular
weight
=
80
Dalton.
amidines. Pyrimidine, which accepts two protons
Dihydropyrimidines are the compounds which are
under extremely acidic conditions (pKa1 1.3 pKa2
obtained by cyclocondensation reaction which
6.9), is much weaker base than pyridine (pKa
having different products. The dihydropyrimidine
5.23), imidazole (pKa 7.2), or amidines in general.
synthetic product has different medicinal uses such
This is because, different imidazole and amidines,
as Antihypertensive, Antibacterial, Antifungal and
antioxidant property. The present review focuses
the addition of a proton does not increase the
on 3, 4--Dihydropyrimidines Thione Their
possibilities for resonance and hence the
Chemistry and Pharmacological Potentials.
resonance energy. It is a unpredictably weaker
base than pyridazine (pKa 2.33). Only one of the
Introduction
Pyrimidine is a six membered heterocyclic ring
nitrogen atoms of the pyrimidine is alkylated by
having two nitrogen (N) atoms in their ring.
alkylating agents, such as methyl sulphate, but the
Pyrimidine having molecular formula of C4H4N2
much
more
potent
agent
and molecular weight = 80 Dalton.
triethyloxoniumborofluoride
alkylates
both
Physical Properties and Structure: Pyrimidine
nitrogen atoms to give a ring bearing two positive
is a colourless compound, having melting point
charges.[1]
22.50C and boiling point 1240C. Its dimensions
Electrophilic Reactions: From the consideration
have been determined by an X-ray diffraction
of the charged structures contributing to the
study of a crystal at -20C and closely look like
resonance hybrids represents pyrimidine and
those of pyridine (six membered hetrocyclics with
pyridine, and the pair electron densities, it is
one nitrogen atom in their ring).
obvious that the position 5 of pyrimidine which
should match up to position 3 of pyridine and be
the most susceptible in the ring to electrophilic
N
attack. Pyrimidine hydrochloride is brominated at
position 5, but no other electrophilic substitution
N
of pyrimidine itself has been claimed. If activating
Pyrimidine is best considered as a resonance
groups, such as hydroxyl or
2
hybrid to which the uncharged equivalent kekule
other positions in the molecule, electrophilic
structures 1 and 2 and the charged structures 3-8
substitution (nitration, nitrosation, diazocoupling)
contribute. The self-consistent pai electon
usually occurs, but only at position 5. [2]
densities, designed for ground state of pyrimidine,
are 0.776, 0.825, and 1.103 for positions 2, 4, and
5, respectively.
====================================
Corresponding Author: Kadam NR
Email id: kadamnagu@gmail.com
Received: 07.11.2013
Revised: 08.12.2013
Accepted: 10.12.2013
1
õ

2. Int. J. Pharm. Res. Sci.,2013,01(1),1-6.
N
O
Br
Br2
N
nitrobenzene
N
ISSN:2348 –0882
H3 C
NH
phLi
NH
Ether
N
N
2 CH 2 OH
N
N
H 3C
O
N
NH
N
H
HO
H5C2
O
H
N
O
O
O
H5C2
NH
N
H
O
BARBITURIC ACID
VERANAL
HN
In addition to this, pyrimidine nucleus is also
found in alloxan, which is well-known for its
O
diabetogenic action in a number of animals. [6]
CH3
O
+
RIBOFLAVIN
THIAMINE
Pyrimidine nucleus is also present in barbituric
acid and its several derivatives e.g. Veranal)
which are used as hypnotics. [5]
HN
O
N
H
NH2
HN
+
NH2
N
KM 4
nO
Acetone
H
N
S
H 3C
Biological Importance of Pyrimidine: In
medicinal chemistry pyrimidine derivatives have
been very well known for their therapeutic
applications. The presence of a pyrimidine base in
thymine, cytosine and uracil, which are the
essential building blocks of nucleic acids, DNA
and RNA is one of the possible reasons for their
activities.[3]
O
O
(CHOH) 3
CH
Ph
(O)
N
HOH 2 C
Nucleophilic Reactions: Positions 2, 4, and 6 of
pyrimidine formally correspond to those of 2 or 4
of pyridine and, in the few cases investigated, are
attacked by nucleophilic reagents such as
sodamide (NaNH2) and phenyl magnesium
bromide (PhMgbr) However; pyrimidine itself is
decomposed by hot aqueous alkali. Pyrimidine is
attacked at the 2- and 4-positions by the 4
nitrophenyl radical. [2]
N
N
H3 C
N
H Ph
N
N
THYMINE
CYTOSINE
URACIL
Vitamins are essential for body. Pyrimidine ring is
found in vitamins similar to riboflavin, thiamine
and folic acid.[4]
O
O
NH
O
N
H
O
ALLOXAN
Dihydropyrimidines - Introduction
The first synthesis of dihydropyrimidines was
reported by Biginelli7 in 1893; however, the
synthetic potential of this heterocyclic synthesis
remained new for fairly some time. In the 1970’s
interest steadily increased, and the scope of the
original cyclocondensation reaction was gradually
unlimited by variation of all the building blocks,
allowing access to a large number of
2

3. Int. J. Pharm. Res. Sci.,2013,01(1),1-6.
ISSN:2348 –0882
multifunctionalized dihydropyrimidines of various
types. Since the late 1980’s, a tremendous
increase in activity has again occurred, as evident
by the growing number of publications and
patents on the subject. This is mainly due to the
fact
that
the
multifunctionalized
dihydropyrimidine
scaffold
(“Biginelli
compounds”) represents a heterocyclic system of
amazing pharmacological efficiency. Since then
several reviews on synthesis and chemical
properties
of
pyrimidinones
have
been
published.The search for new and efficient
methods for the synthesis of pure compounds has
been an active area of research in organic
synthesis. From a modern point of view, Biginelli
procedure is obviously very attractive for
combinatorial chemistry and has been not often
used for parallel synthesis, a new avenue could be
connected with an elaboration of catalytic
procedures.[7]In 1893, P. Bigenelli reported on the
acid catalyzed cyclo-condensation reaction of
ethyl acetoacetate, benzaldehyde, and urea. The
reaction was carried out by simply heating a
mixture of the three components dissolved in
ethanol with a catalytic amount of hydrochloric
acid at reflux temperature. The product of this
novel one-pot, three components synthesis that
precipitated on cooling of the reaction mixture
was identified as 3,4-dihydropyrimidin-2(1H)-one
and this reaction is known as “Biginelli reaction”,
or “Biginelli Condensation”, or as “Biginelli
dihydropyrimidine synthesis”. Since then a
number of improved variants employing new
reagents, catalyst, methodologies and technique
have developed till today.[8’9]
A. Dihydropyrimidines as calcium channel
channel blockers and antihypertensive
Kamaljit et al :
were synthesized 3,4dihydropyrimidine-2(1H)-ones under solvent-less,
mild phase transfer catalytic (PTC) conditions
with tetrabutylammonium hydrogen sulfate and
50% aqueous NaOH as the catalyst and base and
screened for calcium channel blocking activity
based on their ability to relax a membrane
depolarization induced contraction of vascular
smooth muscle. The calcium channel blockers
were compared against nifedipine for their ability
to relax a membrane depolarization induced
contraction. All synthesized compound were
maximally relaxed the KCl-induced contractions
by only 40% with IC50s ranging from 100 to 300
mM.[10]
O
Ar
H5C2
-
NH
N
H 3C
O
C 4 H 9 Br
Hiren et al :
Were synthesize and in-vitro
screening of 3, 4-dihydropyrimidin2 (1H)-one
derivatives for antihypertensive and calcium
channel blocking activity. Nifedipine was used as
standard reference drug for screening of anti
hypertensive and calcium channel blocker. among
all the eight synthesized compounds Compound
6c was found to have better antihypertensive
activity and compound 6f found to have better
calcium channel blocker activity.[11]
R
C H
H N
O
3
R
1
N
H
R= H, Cl
R1= OC2H5, N (C2H5)2, N (CH3)2
Patil et al: were synthesize dihydropyrimidinones
in a three step reaction in presence of hydrazine
hydrate, pyridine as intermediate by using
Microwave
synthesis
.and screened for
antihypertensive activity by non-invasive tail-cuff,
and evaluated by carotid artery cannulation
method for determining the diastolic blood
pressure. Hypertension was induced by DOCAsalt. Test compounds 1-8 exerted comparative
anti-hypertensive activity at 10 mg/kg dose level
compared to nifedipine. Compounds 2, 4 and 8
showed excellent results on evaluation by direct
method. Also Anti-inflammatory activity was
carried out by Carrageenan induced rat-paw
oedema method. Test compounds 3, 4 and 7
exerted
moderate
to
comparative
antiinflammatory activity at the 100 mg/kg dose level
compared to indomethacin.[12]
3

4. Int. J. Pharm. Res. Sci.,2013,01(1),1-6.
O
Ar
ISSN:2348 –0882
-
thiones have been prepared by Mannich reaction
with seven different heterocyclic secondary amino
compounds and formaldehyde. In this reaction
four
different
derivatives
of
3,4dihydropyrimidines-2(1H) thiones have been used
as hydrogen active compounds. These precursors
have been derived by Biginelli reaction of four
aromatic aldehydes, namely benzaldehyde,
salicylaldehyde, anisaldehyde, and vanillin ,
respectively with ethylacetoacetate and thiourea.
All
compounds are screened for in vitro
antimicrobial activity against E coli and B.subtilis.
and. antifungal activity against A.niger and C.
Albicans. All compounds shows promising
antimicrobial activity against both bacterial and
[15]
fungal microorganisms.
NH
NH
SO 2
NH
H3C
N
H
X
CH3
B. Dihydropyrimidines as antibacterial
and antifungal evaluation
Okram et a l : synthesized dihydropyrimidinones
using Copper (II) chloride in the absence of any
solvent and in vitro evaluate of the antifungal
activities against the radial growth of three fungal
species viz., Trichoderma hammatumTrichoderma
koningii and Aspergillus niger. Among all six
synthesized compounds 4a, 4c, 4e shows highest
growth inhibition. [13]
O
R1
H5C2
R2
R1
O
H
H5C2O
NH
NH
H3C
H3C
N
X
H
X= O, S R1= C6H5, 2-HOC6H4, 4-Me2NC6H4
Mohammad et al :
were synthesized
Dihydropyrimidinones and their thioanalogue by
three component condensation of Urea/thiourea
ethylacetoacetate and substituted aldehydes.
Comparison shows that all the synthesized
compounds are significantly active. All
compounds have been screened for their
antifungal activity against A. niger and C.
Albicans using agar well diffusion method against
ciclopiroxolamine. . From comparative activity
study, it noticed that thione compounds showed
more activity than pyrimidinone compounds. [14]
S
N
H
R1= H, OMe R2= H, OMe, o
Jayakumar et al: were synthesize substituted 3,4dihydropyrimidin-2(1H)-ones
(DHP)
by
cyclocondensation
reaction
between
3,4dimethoxybenzaldehyde ( veratraldehyde), active
methylene compounds (acetyl acetone or
acetoacetic ester) and urea / thiourea in presence
of CuCl2.2H2O and HCl by grindstone solvent
free and ecofriendly technique. These synthesized
derivatives have been tested for antibacterial
activity against Micrococcus luteus , Escherichia
coli & Pseudomonas aeruginosa and for antifungal
activity against Aspergillus niger, Candida
albicans & Candida kefyr . [16]
OCH
R2
3
OCH
R1
HN
X
O
CH3
O
R
O
N
H
3
NH
H 3C
CH3
N
H
R= CH3, C2H5
R1= H, No2
R2=OMe, H, Cl X=O, S
Shah et al : were synthesized Four series of NMannich base of 3,4-dihydropyrimidines 2(1H)
C. Dihydropyrimidines
activity
4
Z
Z= O ,S
as
Antioxidant

5. Int. J. Pharm. Res. Sci.,2013,01(1),1-6.
ISSN:2348 –0882
Nidhi G. et al :
were synthesized 3,4Dihydropyrimidin-2(1H)-one
derivatives
by
Organocatalysed microwave assisted synthesis
using oxalic acid as a new, efficient, and
environmentally benign catalyst. Antioxidant
properties of synthesized compounds were
evaluated by three methods, viz., radical
scavenging
effect
on
2,2-diphenyl-1picrylhydrazyl radicals, reducing power and Fe2
Chelating activities. Amongst the 12 synthesized
compounds, four were found to have significant
antioxidant activity. [17]
;
R
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, Elizabeth
Poremsky, Jazmyne Lowery, Robert S.
Moreland:
N1-Alkylated
3,4dihydropyrimidine-2(1H)-ones:
Convenient one-pot selective synthesis and
evaluation of their calcium channel
blocking activity, European Journal of
Medicinal Chemistry (2009); 44: 1997–
2001;
11. Hiren M. Marvaniya, Palak K. Parikh and
Dhrubo Jyoti Sen: Synthesis and in-vitro
screening of 3, 4- dihydropyrimidin2(1H)-one derivatives for antihypertensive
and calcium channel blocking activity.
Journal of Applied Pharmaceutical
Science2011; 01 (05): 109-113.
12. P. A. Patil, R. P. Bhole, R. V. Chikhale,
K. P. Bhusari: Synthesis of 3,4Dihydropyrimidine-2(1H)-one Derivatives
using Microwave for their Biological
screening.
International
Journal
of
ChemTech Research 2009;Vol.1: No.2, :
373-384 ,
13. Okram Mukherjee Singh a, Sarangthem
Joychandra Singh, Mutum Babita Devi ,
Laitonjam Nalini Devi, Nameirakpam
Irabanta Singh, Sang-Gyeong Lee:
Synthesis and in vitro evaluation of the
antifungal
activities
of
dihydropyrimidinones.
Bioorganic
&
Medicinal Chemistry Letters 2008; 18:
6462–6467.
14. Mohammad Aslam and Shaifali Verma:
Biological activity of newly synthesized
substituted Dihydropyrimidinones and
Thione.
International
Journal
of
ChemTech Research2012; Vol.4, No.1:
109-111.
15. TB Shah, A Gupta, M R Patel, V C
Chaudhari, H Patel &V C Patel: Synthesis
and in vitro study of biological activity of
heterocyclic N-Mannich bases of 3,4dihydropyrimidines -2(1H)thione. Indian
journal of chemistry2010; Vol.49B:578586.
1
O
RO
NH
Me
R= C2H5, CH3
N
H
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 and
Pharmacological Potential. Asian Journal
of Biochemical and Pharmaceutical
Research2012; Issue 1 (Vol. 2) ISSN:
2231-2560.
2. Ahluwalia and Madhuri Goyal. Text Book
of Organic chemistry. ISt.ed: (2001); 777717.
3. Raghav Mishra and Isha Tomar:
Pyrimidine: The Molecule Of Diverse
Biological and medicinal importance;
IJPSR (2011), Vol. 2, Issue 4.
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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.
5

6. Int. J. Pharm. Res. Sci.,2013,01(1),1-6.
ISSN:2348 –0882
16. S. Jayakumar and T. K. Shabeer:
Multicomponent Biginelli Synthesis of 3,
4-dihydropyrimidin-2(1H)-ones
by
grindstone technique and evaluation of
their biological properties. Journal of
Chemical
and
Pharmaceutical
Research2011; 3(6):1089-1096.
17. Nidhi Gangwar, Virendra Kumar Kasana:
3,
4-Dihydropyrimidin-2(1H)-one
derivative: Organocatalysed microwave
assisted synthesis and evaluation of their
antioxidant activity. Medicinal Chemistry
Research 2012; DOI 10.1007/s00044-0129987.
.
6