Mar25j.pdf

REVIEW ARTICLE
Biological and medicinal significance of
pyrimidines
K. S. Jain1,*, T. S. Chitre1, P. B. Miniyar1, M. K. Kathiravan2, V. S. Bendre1,
V. S. Veer2, S. R. Shahane1 and C. J. Shishoo3
1Sinhgad College of Pharmacy, Pune 411 041, India
2Poona College of Pharmacy, Pune 411 038, India
3L.M. College of Pharmacy, Ahmedabad 380 009, India
This article outlines the biological significance of one
of the most important heterocycles, the pyrimidine.
An attempt has been made to cover most of the physio-
logically as well as medicinally important compounds
containing pyrimidine and its derivatives.
(7) Folic acid (8) Barbitone
Keywords: Heterocycles, Pyrimidines: biological signi-
ficance, Pyrimidines: medicinal significance. Medicinal significance
Biological significance
During the last two decades, several pyrimidine derivatives have been developed as chemotherapeutic agents and have Pyrimidines have a long and distinguished history extend- ing from the days of their discovery as important constituents of nucleic acids to their current use in the chemotherapy of AIDS. Antineoplastics and anticancer agents Alloxan (1) is known for its diabetogenic action in a
number of animals1. Uracil (2), thymine (3) and cytosine
There are a large number of pyrimidine-based antimeta- (4) are the three important constituents of nucleic acids.
bolites. They are usually structurally related to the endo- genous substrates that they antagonize. The structural modification may be on the pyrimidine ring or on the pendant sugar groups. One of the early metabolites prepared was 5-fluorouracil3,4 (5-FU, 9a), a pyrimidine derivative. 5-
Thiouracil (9b) also exhibits some useful antineoplastic
(1) Alloxan (2) Uracil (3) Thymine (4) Cytosine
The pyrimidine ring is found in vitamins like thiamine2
(5), riboflavin2 (6) and folic acid (7)2. Barbitone1 (8), the
first barbiturate hypnotic sedative and anticonvulsant is a pyrimidine derivative1. (9a), X = O, R = F, R1 = H, 5-fluorouracil
(9b), X = O, R = SH, R
The antineoplastic compounds6 possessing the guanine nucleus (10) like azathioprine7 (11), mercaptopurine8 (12),
(5) Thiamine (6) Riboflavin
thioguanine9 (13), tegafur10 (14), etc. were discovered after
formulation of the antimetabolite theory by Woods and Fildes in 1940. These drugs prevent the utilization of *For correspondence. (e-mail: [email protected]) CURRENT SCIENCE, VOL. 90, NO. 6, 25 MARCH 2006 binose having a beta configuration. It is mainly used as an anticancer agent and also exhibits significant therapeu- tic effects in patients with herpes virus infections and Gemcitabine (21), a pyrimidine antimetabolite, shows
excellent antitumour activity against murine solid tu- (10) (14) Tegafur
(11) Azathioprine
(12) Mercaptopurine –H –H
(13) Thioguanine –H –NH
(21) Gemcitabine
There are many more in recent times, like mopidamol11
(15), nimustine12 (16), raltitrexed13 (17), uramustine14 (18)
and trimetrixate15 (19).
2-Thiouracil (9c) and its alkyl analogue, thiobarbital (9e)
are effective drugs against hyperthyroidism. Propylthio- uracil (9d) is used as a drug for hyperthyroidism with
(15) Mopidamol (16) Nimustine
(9c–e)
(9c), R = R1 = R2 = H, X = S; 2-thiouracil (9d), R = R1 =
H, R2 = C3H7, X = S; propylthiouracil (9e), R = R1 =
(17) Raltitrexed
Antifolates, antibacterials and antiprotozoals In 1948, Hitchings made an important observation that a large number of 2,4-diaminopyrimidines and some 2-amino- 4-hydroxypyrimidines are antagonists of folic acid19. (18) Uramustine (19) Trimetrexate glucuronate
Since then, a large number of 2,4-diaminopyrimidines have been synthesized as antifolates. It was eventually proved that these pyrimidines are inhibitors of the enzyme dihydrofolate reductase (DHFR)20,21. Notable amongst the 2,4-diaminopyrimidine drugs are pyrimethamine (22), a
selective inhibitor of the DHFR of malarial plasmodia;
trimethoprim (23), an antibacterial drug which selectively
inhibits bacterial DHFR and most importantly, the very potent but non selective DHFR inhibitors, methotrexate
(24a) and aminopterin (24b), both used in cancer chemo-
therapy22. 3′,5′-Dichloromethotrexate (24c), which is less
(20) Ara-C
toxic and more readily metabolized than methotrexate, has recently been introduced for anticancer therapy23. Brodi- 1-β-D-Arabinosylcytosine16 (Ara-C, 20) is also an example
moprim (25) is also found to be an effective antibacterial
of a pyrimidine antimetabolite in which the sugar is ara- CURRENT SCIENCE, VOL. 90, NO. 6, 25 MARCH 2006 (22) Pyrimethamine (23) Trimethoprim
Sulfadiazine (27a) H H H
Sulfamerazin (27b) H CH
Sulfadimidine (27c) H CH3 CH3
Sulfametoxydiazine (27f) OCH
Methyldiazine (27e) CH
(24a) R = CH
(24b) R = X = H; Aminopterin
(24c) R = CH3, X = Cl; 3′,5′-dichloromethotrexate
(27d) Sulfadimethoxine
(25) Brodimoprim
(28) Sulfamethoxine

In 1959, sulfadimethoxine29 (27d) was introduced with a
Pyrimidine derivatives of sulfa drugs, namely sulfadiazine, half-life of approximately 40 h. The related 4-sulfonami- sulfamerazine and sulfadimidine are superior to many dopyrimidine, sulfamethoxine29 (28) having two methoxy
other sulfonamides and are used in some acute UT infec- groups in 5 and 6 positions, has by far the longest half- tions, cerebrospinal meningitis and for patients allergic to life of about 150 h. Methyldiazine29 (27e) has a half-life
of 65 h. Also, sulfamethoxydiazine29 (27f) possesses good
. Sulfonamide–trimethoprim combinations are used extensively for opportunistic infections in patients half-life. A new broad-spectrum sulfonamide, sulfa- with AIDS26. Sulfadoxine27 (26a), a short and intermedi-
methomidine29 (29) is relatively nontoxic and patients do
ate acting sulfonamide with a half-life of 7–9 days is used not need extra fluid intake or alkalization. Sulfacytine29
(30) has been reported to be 3–10 times more potent than
for malarial prophylaxis. Sulfisomidine (26b) with a half-
life of 7 h is used as a combination sulfa therapy in vet- erinary medicine28. Sulfadiazine (27a), sulfamerzine
(27b) and sulfadimidine (27c) possess good water solubi-
lity and therefore carry minimum risk of kidney damage, which makes them safe even for patients with impaired (29) Sulfamethomidine (30) Sulfacytine
Sulfadoxine (26a)
Recently, pyrimidine derivatives have generated wide-spread interest due to their antiviral properties. 5-Iodode- Sulfisomidine (26b) 3
oxyuridine30 (31) is an antiviral agent of high selectivity.
CURRENT SCIENCE, VOL. 90, NO. 6, 25 MARCH 2006 (retroviruses) that are the causative agents of AIDS and T-cell leukaemia. It is used in AIDS and AIDS-related complex (ARC) to control opportunistic infections by raising absolute CD4+ lymphocyte counts. Also, zalcit-
abine36 (38) is another useful alternative drug to zi-
dovudine. It is given in combination with zidovudine, when CD4+ cell counts fall below 300 cells/mm3. Didano- sine37 (39) is a purine dideoxynucleoside, which is an
analogue of inosine. Didanosine inhibits HIV RT and exerts (31) 5-Iododeoxyuridine
a virustatic effect on the retroviruses. Combined with zido- vudine, antiretroviral activity of didanosine is increased. IDU (5-iodo-2′-deoxyuridine) (32a) has been extensi-
Stavudine37 (40) is a pyrimidine nucleoside analogue that
vely utilized for viral infections. 5-Trifluromethyl-2′-de- has significant activity against HIV-1 after intracellular oxyuridine (F3 TDR, 32b) has been found useful against
conversion of the drug to a D4T-triphosphate. It is more infections resistant to IDU therapy30. Ara-A 9-β-D-arabi- effective than zidovudin or didenosine for treatment in nofuranosyl adenine (33), a relatively new antiviral drug,
patients for delaying the progression of HIV infection. It is effective against herpes infections of eye, brain and is recommended for patients with advanced HIV infection. skin. It is especially effective against IDU-resistant herpes Abacavir sulfate37 (41) was approved in 1998 as a NRTI
(Nucleoside Reverse Transcriptase Inhibitor) to be used in combination with other drugs for the treatment of HIV and AIDS. The major use of abacavir appears to be in (32) (33) Ara-A (34) Retrovir
(32a) X = I, 5-iodo-2′-deoxyuridine
(35a) Acyclovir
(32b) X = CF
Some purine nucleosides are equally noteworthy. Retro- (35b) Ganciclovir
vir (AZT-16, 34) is a potent inhibitor of the in vivo repli-
cation and cytopathic effects of HIV and has been recently approved for use against AIDS and severe ARC31. (35c) Famicivlovir
At present Acyclovir (35a) is the only remedy for genital
herpes. The oral formulation of Acyclovir is effective against both first and second-degree recurrence-genital (35d) Valaciclovir
herpes with minimal side effects32. Ganciclovir33 (DHPG- 2, 35b) has shown good in vivo activity against HCV
(35e) Penciclovir
Several members of a series of acyclic nucleosides, which contain a fused pyrimidine ring (mainly purine), are found to be effective antivirals. Famiciclovir (35c)
and valacyclovir (35d) are drugs used for several DNA
viruses, including Hsv types 1 and 2, Varicella-zoster virus and Epstein-Barr virus34. Penciclovir (35e)35 is useful for
topical treatment of recurrent herpes, Libialis. Cidofovir (36b)35, an antimetabolite for deoxycytosine triphosphate
is used for treatment of cytomegalovirus (CMV) in AIDS patients. Lamivudine (36a)35 is an effective anti-AIDS
(36a) Lamivudine
drug when used in combination with zidovudine (37)35.
Zidovudine36 is an analogue of thymidine in which the azido group is substituted at the 3-position of the dide- (36b) Cidofovir
oxyribose moiety. It is active against RNA tumour viruses CURRENT SCIENCE, VOL. 90, NO. 6, 25 MARCH 2006 (45) Plicacetin
(37) Zidovudine (38) Zalcitabine
(46) Puromycin
NH(CH ) S(CH )
(39) Didanosine (40) Stavudine (41) Abacavir
There are few examples of pyrimidine antibiotics. The sim- plest of all is bacimethrin (5-hydroxymethyl-2-methoxy- pyrimidin-4-amine) (42), which is active against several
(47a) Phleomycin
staphylococcal infections38. Gourgetin (43), a cytosine
derivative is active against mycobacteria as well as several Gram-positive and Gram-negative bacteria39. There are more derivatives of cytosine, namely amicetin (44) and
plicacetin (45), which exhibit activity against acid fast
and Gram-positive bacteria as well as some other organisms38. Puromycin (46) has a wide spectrum of antitrypanosomal
activity. Aminoglycoside antibiotics phleomycin (47a),
bleomycin (47b) and related families are wide-spectrum
antibiotics containing the pyrimidine ring. Another anti- biotic tubercidine (48) is reported to exhibit antitumour
properties39. In addition, they have antineoplastic activity. (47b) Bleomycin
Bleomycin is already in clinical use against certain tumours like Hodgkin’s lymphoma and disseminated testicular (42) Bacimethrin (43) Gourgetin
(48) Tubercidine
Pyrimidines also exhibit antifungal properties. Flucytosine (44) Amicetin
(49)41 is a fluorinated pyrimidine used as nucleosidal anti-
CURRENT SCIENCE, VOL. 90, NO. 6, 25 MARCH 2006 REVIEW ARTICLE fungal agent for the treatment of serious systemic infections caused by susceptible strains of candida and cryptococcus42.
Hexitidine43 (50) is mainly used for the treatment of
Sedative/hypnotic/antiepileptic agents: Agents of the anxio- lytic, sedative and hypnotic group include a wide variety of barbiturates (54a–i) used as sedative and hypnotics and
are classified as drugs having short, intermediate and long duration of action47,48. Allobarbital (54a), aprobarbital
(54b), pentobarbital (54e), phenobarbital (54g) and seco-
barbital (54i) are frequently used clinically as hypnotic
barbiturates49. Hexobarbital (54c), cyclobarbital (54d) and
propallylonal (54f) are some of the current drugs in the
(49) Flucytosine (50) Hexitidine
market used as sedative hypnotics50. Barbiturates as seda-tive hypnotics have a long and fascinating history. In fact Eli Lilly51 patented secbutabarbital (54h) in 1932, while
barbitone (8), the first of the barbiturates1 was introduced
These drugs have the ability of ridding the body of para- sitic worms. Pyrantel pamoate (51) is a depolarizing neu-
romuscular blocking agent that causes spastic paralysis in helminthes and is employed in the treatment of infesta-tions caused by pinworms and roundworms44. (51) Pyrantel pamoate
(54a) Allobarbital
Capreomycin (52) produced by Streptomyces capreolus is
(54b) Aprobarbital
a second-line bacteriostatic antituberculin drug contain- (54c) Hexobarbital
(54d) Cyclobarbital
(52) Capreomycin
(54e) Pentobarbital
Viomycin (53) is more tuberculostatic than p-amino-
salicyclic acid. It is effective in the treatment of experi- (54f) Propallylonal
(54g) Phenobarbital
CHNHCONH
(54h) Secbutabarbital
(54i) Secobarbital
(53) Viomycin
CURRENT SCIENCE, VOL. 90, NO. 6, 25 MARCH 2006 Anxiolytic agents: Few of the pyrimidine derivatives are Saxitoxin58 (60) is a naturally occurring pyrimidine con-
also used as anxiolytics. Most important of these is buspi- taining anaesthetic agent, but is too toxic to be of clinical rone (55), indicated in the management of anxiety disor-
use. Saxitoxin is isolated from some marine dinoflagellates. ders accompanied with or without depression. It lacks sedative, anticonvulsant and muscle-relaxant effects and Diuretics, uricosurics: Several xanthine derivatives (61)
most importantly abuse potential52. Buspirone lacks affin- containing fused pyrimidine ring systems like caffeine60 ity to benzodiazepine receptors, but binds avidly to one (61a), etamiphylline61 (61b), lomiphylline62 (61c), eto-
subclass of serotonin receptors, the 5-HT1A subtype53,54. Ri- phylline63 (61d), theophylline60 (56e) and theodrendaline64
tanserin (56), a 5HT2 antagonist with anxiolytic activity
(61f) are known to promote a weak diuresis by stimula-
tion of cardiac function and by a direct action on the A simple pyrimidine derivative, mezilamine (57) is
nephron, acting as adenosine receptor antagonists60. (55) Buspirone (56) Ritanserin
(61a) Caffeine
(61b) Etamiphylline

(61c) Lomiphylline
(61d) Etophylline
(61e) Theophylline
(57) Mezilamine
(61f) Theodrendaline
Risoperidone (58) is an antipsychotic drug, which is a
structural hybrid of butyrophenone and can be used as anxiolytic, antidepressant and antiparkinsonian drug57. There are a few examples of diuretics which contain a pyrimidine ring. Noteworthy are quinethazine (62a), meto-
lazone (62b)65 and triamterene (63)66.
(58) Risoperidone
(62) (63) Triamterene
Pyrimidine anaesthetics: Thimylal (59) is a short acting
(62a) R = C
general anaesthetic drug, which is also a pyrimidine ana- (62b) R = CH
Antihypertensives: Several pyrimidine ring-containing drugs have exhibited antihypertensive activity. Prazosin (64a), a quinozoline derivative, is a selective α1-adrener-
gic antagonist67,68. Its related analogues bunazosin (64b)69,
(59) Thimylal (60) Saxitoxin
terazosin (64c)70 and trimazosin (64d)71 are potent anti-
CURRENT SCIENCE, VOL. 90, NO. 6, 25 MARCH 2006 REVIEW ARTICLE hypertensive agents. Another quinazoline derivative, ketanserin (65)72 having a similar effect is an antagonist
of both α1-adrenergic and serotonin-S2 receptors. Its mechanism of action however is still controversial. A triaminopyrimidine derivative, minoxidil (66), whose
mechanism of action and therapeutic action are similar to Prazosin, has been introduced in therapy for its side effects, in the treatment of alopecia, male baldness73. (69a) Pentifylline
(69b) Pentoxifylline
(69c) Propentophylline
Other derivatives like xantinol nicotinate77 (70b), a vaso-
dilator with general properties like nicotinic acid used in cerebral and peripheral vascular disorders and pimephyl- line (70a) and pyridophylline78 (70c) are noteworthy.
(64a) Prazosin (64b) Bunazosin
(70a) Pimefylline
(64c) Terazosin (64d) Trimazosin
(70b) Xantinol nicotinate
(70c) Pyridofylline
A new dopamine receptor stimulant, pirebidil (71)79 is re-
ported to have produced significant improvement in ADL (65) Ketanserin (66) Minoxidil
(Activity of Daily Living) in patients suffering from Besides these, some more pyrimidine derivatives given below were found to be antihypertensives74,75. (71) Piribedil
(67) Alfuzocin (68) Urapidil
Cardiotonics/bronchodialators: Several xanthine deri- vatives theophylline (61e), aminophylline80 (72a) and pro-
Alfuzocin74 (67), a prazocin analogue and an α1-adreno-
xyphylline80 (72b) exhibit good bronchodilator activity.
ceptor antagonist as well as urapidil75 (68) are used espe-
cially in urinary obstruction caused by benign prostate Vasodilators: A series of xanthine derivatives are used as peripheral and cerebral vasodilators. Especially, pentifyl- line (69a) and pentoxyphilline (69b) are used in cardio-
(72a) Aminophylline (72b) Proxyphylline
CURRENT SCIENCE, VOL. 90, NO. 6, 25 MARCH 2006 Taziphylline (73) is ten times more potent than either
astemizole or terfenadine in its affinity for H binding site and appears to be devoid of CNS activity81. Another pyrimidine containing antihistaminic drug, teme- lastine (73a) is comparable to mepyramine82. Radio-
labelled studies have indicated that it does not penetrate (76a) Acetiamine
the CNS appreciably. Icotidine (73b), a structural ana-
logue of temelastine lacks CNS activity and is a dual an- (76b) Bentiamine
(73) Taziphylline
(76c) Fursultiamine
Afloqualone88 (77) has been evaluated as a successful
anti-inflammatory agent with lower back pain patients. Epirazole89 (78), another NSAID, is suggested to be a
(73a), R1 = Br, R2 = CH3; temelastine
COX-2 inhibitor. Ademetionine90 (79) is primarily used in
(73b), R1 = H, R2 = OCH3; icotidine
conjunction to glucosamine and chondroitin therapy. Oc- totiamine91 (80), a vitamin B1 derivative also exhibits anti-
Pemirolast84 (74), a new oral nonbronchodilator antihista-
minic agent is also a pyrimidine derivative. It has demon- strated sufficient antihistaminic activity to warrant its use in severe asthma. Another compound, piprinhydrinate85 (75) is also a pyrimidine derivative.
(77) Afloqualone (78) Epirizole
(74) Pemirolast (75) Piprinhydrinate
(79) Ademetionine (80) Octotiamine
Acetiamine86 (76a), bentiamine86 (76b) and fursultia-
mine87 (76c) are new lipid-soluble forms of thiamine (vita-
1) having therapeutic use in beriberi, polyneuritis, encephalopathy, pain, malnutrition and alcoholism and especially in the treatment of long-standing insulin-depen-dent diabetes mellitus. Fursultamine has been reported to inhibit the arachadonic acid cascade-line activation and reverse the increase in CBF (Coronary Blood Flow). (81) Proquazone
CURRENT SCIENCE, VOL. 90, NO. 6, 25 MARCH 2006 REVIEW ARTICLE
Proquazone92 (81), a condensed pyrimidin-2-one deriva-
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Received 11 July 2005; revised accepted 11 December 2005 CURRENT SCIENCE, VOL. 90, NO. 6, 25 MARCH 2006

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