Preparation of fused thiadiazolo- and imidazobenzothiazoles from 2-aminobenzothiazoles. Their fungicidal activity

Article abstract of DOI:10.3987/COM-97-7839

A regioselective [2+3] cyclocondensation between chlorocarbonylsulfenyl chloride (3) and 2-aminobenzothiazoles gave 3H-1,2,4-thiadiazolo[3,4-b]benzothiazol-3-ones (1). Some heterocycles (1) and their isosteric known 5-substituted 2-methyl-imidazo[2,1-b]benzothiazoles (2) which were prepared from 2-aminobenzothiazoles via two steps, showed significant fungicidal activities.

Full text of DOI:10.3987/COM-97-7839

Mukhtyar. S. Saini et al. / International Journal of Pharma Sciences and Research (IJPSR)
A REVIEW: BIOLOGICAL
SIGNIFICANCES OF HETEROCYCLIC
COMPOUNDS.
1
1
2
3
Mukhtyar. S. Saini, Aran Kumar , Jaya Dwivedi , Rakesh Singh
1
Department of Chemistry, Govt. G. M. Science College, Jammu, Jammu,180001, India.
2
Department of Chemistry, Banasthali University, Jaipur, Rajasthan, 304022, India.
3
Department of Chemistry, Govt. D.C.WOMEN.Kathua, J&K.India
1
Address correspondence to Mukhtyar. S. Saini , Department of Chemistry, Govt. G. M. Science, College,
Canal Road Jammu, Jammu, 180001, India
E-mail: mukhtyar_saini@yahoo.com.
Abstract
Heterocyclic chemistry offers an example for the lack of distinct demarcations; in fact, it pervades the plurality
of the other chemical disciplines. Heterocycles are inextricably woven into the life processes. The vital interest
of the pharmaceutical and agrochemical industries in heterocycles is often connected with their natural
occurrence. Synthetic chemistry provides cornucopia of heterocyclic systems. More than 90% of new drugs
contain heterocycles and the interface between chemistry and biology, at which so much new scientific insight,
discovery and application is taking place is crossed by heterocyclic compounds. This review article covers the
most active heterocycles that have shown considerable biological actions as antifungal, anti-inflammatory,
antibacterial, anticonvulsant, antiallergic, herbicidal, anticancer activity
Key words: Heterocyclic, biological activities.
INTRODUCTION
Medicinal chemistry had its beginning when chemists, pharmacist and physicians isolated and purified active
principles of plants and animals’ tissues and taken from micro-organism and their fermentation products.Some
of these chemicals has been associated with therapeutic properties: Medicinal chemistry which has leaned on the
classical fields of chemistry, especially organic chemistry, biology and some area of physics. A limited number
of natural and synthetic products and serve directly as therapeutic agents although lack of specificity frequently
limits their application in human and veterinary medicines and in analogous pesticidal and other uses in
agriculture. By dissecting the structure of these products chemically, one arrives at its therapeutically significant
molecular sections, the pharamacophores, the portion that can be deleted are of no interest as components of
drug action; they are regarded as the result of the biosynthetic efforts on the parent organism to construct
materials for its own matebolic or defensive purposes.
Most of the drugs belong to the class of heterogenius compounds. Heterocyclic compounds played a vital role in
the metabolism of all living cells; large number of them are five and six membered heterocyclic compounds
having one to three heteroatoms in their nucleus. The compounds may be pyrimidine and purine basis of
genetic material DNA, and these heterocyclic compounds may be isolated or fused heterocyclic systems.
Some of the common heterocyclic compounds used in the medicines are as amino acids like proline, histidine
and tryptophan, the vitamins and coenzymes precursors such as thiamine, riboflavin, pyridoxine, folic acid,
biotin, B12 and E families of the vitamins. There is a vast number of pharmacologically active heterocylic
compounds, many of which are in regular clinical use.The pyrimidines and its derivatives have a vital role in
biological properties. 2- Sulphanilamidopyrimidines viz. Sulphadiazine , Sulphamethoxydiazine and
Sulphadiazine are well known antibacterial agents.
Pyrimidinetrinitrones commonly known as barbituric acids have important role in the biologically field. 5-
alkylated pyrimidinetrinitrones have been reported to show antispasmodic,muscel relaxant and anticonvulsant
activity.
Substituted 1,3,4-oxadiazoles have shown multiflarious biological activities. 2-Acetamide-5-phenyl- 1, 3, 4-
oxadiazole have antimitotic, analgetic diuretic and antiemetic properties . Some of them also acts as hypnotics,
sedative and antidiarrhael agents .
Literature survey shows that a number of heterocyclic compounds having condensed ring system possess
various types of physiological activities. Condensed triazolo- pyrimidines and N-benzylidene derivatives
exhibits antifungal [1-4], anti-inflammatory [5-12],antibacterial[13-20] , anticonvulsant[21-24], antiallergic [25-
3
3], herbicidal[34-41]. anticancer activity[42-45].
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Biological activities
-Antifungal activity
1
Fungi are heterotropic microorganisms that are distinguished from algae by lack of photosynthetic
ability.Fungi includes both yeast and moulds.The former are spherical,oval and mucosid colonies in agar
medium and the latter consists of elgonated cells that usually reproduce by budding and forming branches of
cells.
a).F.Russo et al have synthesized thiadiazolo pyrimidines(i)and their hydrazines(ii) R=CF
3
C
6
H
4
,2-OEtC
6
H
4
2 6 4
and 4-NO C H .
CONHNH2
Ph
N
N
N
N
O
O
S
N
S
N
R
(i)
(ii)
b).Ahluwalia et al have synthesized 5-(3',4'-dihydro-2',2',8'-trimethyl-2'H-1'-benzopyran-7-yloxymethyl)-4-phenyl-1,3,4-triazole-3(4H)-
thiol (III)which shows significant antifungal activity.R=C
6
H
5
,mcl-C
6
H
4
, pcl-C
6
H
4
,m-or pCH
3
- C
6
H
4
3 6 4 1 3
, pCH O- C H .R =CH ,
C
6
H
5
,R
2
=H,CH .
3
N
NH
CH3
R1
O
O
C
N
R
S
H
2
R2
(iii)
c).Gogia et al have synthesized 1,3,4-oxa / thiadiazolo –(3,2-a)pyrimidin-5-one (iv) which shows antifungal activity.x=O,S.
O
R1
Cl
N
N
X
N
R
Cl
d).Ahluwalia et al have studied the N-benzylidene-3, 4-dihydro-2,2,8-trimethyl-2H-1-benzopyran-7-yloxyacetie acid hydrazide (v) and
(
iv)
found antifungal R
1
=R
2
3 6 5 3 4 3
=CH ,C H ,R =R =H,CH .
R3
O
CH3
R1
O
C
NH N=CH2
R4
O
C
H
2
R2
(
v)
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6 5 2 6 5
e).Singh et al have synthesized 1,3,4-oxadiazolo-(3,2-a)-s-triazin-7-thione(vi).and found antifungal.In compound(v), R= C H CH -,C H ,O-
1
ClC
6
H
4
,m-MeC
6
H
4
,p-Mec
6
H
4
6 5 6 4
;R =C H ,O- ClC H
R1
N
N
N
S
N
O
R
(
vi)
f).Dutta et al have synthesized 2-substituted 1,3,4-oxadiazolo-[3,2-a]-1,3,5-triazin-5-(6H,7H)-thione derivatives(vii).and found
antifungal.In compound (vii), R= C
6
H
5
,4-BrC
6
H
4
6 4 6 4 6 4 2 6 4 2 6 4
,4-ClC H ,2-ClC H ,3- ClC H ,2-No C H ; 3-No C H .
S
R
N
N
N
Cl
N
O
Ph
Cl
(vii)
6 4
g).Dhar et al have synthesized 1,3,4-oxadiazolo-[3,2-a]- 1,3,4-dithiazines (viii). and found antifungal.In compound (viii) Ar=2- ClC H ,
Ar'=2- ClC
6
H
4
2
OCH .
NAr'
S
N
N
S
O
Ar
(viii)
2
. Anti-inflammatory :
Anti-inflammatory refers to the property of a substance or treatment that
reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing
inflammation as opposed to opioids, which affect the central nervous system. Non-steroidal anti-inflammatory
drugs (NSAIDs), Some common examples of NSAIDs are: aspirin, ibuprofen, and naproxen. The newer specific
COX-inhibitors - although, it is presumed, sharing a similar mode of action - are not classified together with the
traditional NSAIDs. Long-term use of NSAIDs can cause gastric erosions, which can become stomach
ulcers and in extreme cases can cause severe haemorrhage, resulting in death. The risk of death as a result of use
of NSAIDs is 1 in 12,000 for adults aged 16–45. The risk increases almost twentyfold for those over 75. Other
dangers of NSAIDs are exacerbating asthma and causing kidney damage. Apart from aspirin, prescription and
over-the-counter NSAIDs also increase the risk of myocardial infarction and stroke.
a).J.A. Beres and Coworkers have synthesized the compound associated with anti-inflammatory activity. Pyrido[2, 3,- d] pyrimidinone
derivatives have been found to possess anti-inflammatory activities. In compound (I), R =H, halo, alkyl, R =Ph, Cyclohexyl, alkyl, OH.
1 2
O
N
R1
N
N
|
O
R2
(
ix)
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b). Thomas et al have synthesised 2-(hydroxymethy1 )- 5-pheny1-1, 3, 4-oxadiazoles (x) and found that these show antiinflammatory
1
activities in mice , rats and guineapigs. In compound (x) , R =H, CONH
2
OR CONHMe.
1
O
CH OR
2
N
N
(
x)
c).Lewis et al have synthesised 3-Subtstituted - Pyrido-[3, 4-e ]- as-triazines (xi), (xii). These compounds showed antiinflammatory activity.
N
H
N
N
NH
N
N
N
CH3
N
CH3
(
xi)
(xii)
d).Kim et al have reported 7-phenyl pyrazolo-[1, 5-a]-1, 3, 5-triazine derivatives as anti-inflammatory agents (xiii) where R= Thia alkyl ,
1
R =Substituted amino, N-heterocycloalkyl.
R1
N
N
N
N
Ph
R
(xiii)
e).Abdle et al have synthesised some noval 1,3,4-oxadiazole derivatives (xiv), (xv). In compound xv R=4-ClC
MeO) ,4-(Me N)C
6 4 6 4
H ,4-MeOC H ,3,4-
(
2
C
6
H
3
2
6
H
Ph
N
N
N
NAc
N
Ph
OCH2
H
O
R
(xiv)
Ph
N
N
N
N
Ph
N
OCH
2
O
R
(xv)
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f).Joshi et al have synthesised somefluorine containing pyrazolo[5, 1,-C]- 1, 2, 4-triazine (xvi) whereR=3,4-ClFC
6
H
3
Ph
N
N
N
R
N
R1
O
(
xvi)
1
2
g).Heilman et al have synthesized 1,2,4-triazolo [4, 3-b]-1, 2, 4-triazines (xvii) where R =H,alkyl,alkoxyalkyl,haloalkyl,R = H, alkyl,
3
pyridyl, R = alkyl, pyridyl,haloalkyl
R1
R2
N
N
N
N
R3
N
(
XVII)
3.Antibacterial:
Bacteria are the simplest and smallest unicellular organisms found individually or in
clusters. The multitude of highly effective and relatively non-toxic drugs available for the treatment of bacterial
infections have provided tough competition for the medicinal chemist,attempting synthesis of new antibacterial
agents.
a).Sen Gupta et al have synthesized (xviii),some triazine derivatives and found antibacterial agents.
R
R2
N
O
O
N
C - NH
NH -
S
CH2
xviii
C
N
N
R
b).Desai et al have synthesized(xix),2,4-bis(4-methoxy-anilino)-6-(N-aryl-thiourido-N-amino-acyl)-1,3,5-
triazine derivatives and found antibacterial agents.
c).Dutta et al have synthesized 2,5-disubstituted-1,3,4-oxadiazolo/ thiadiazolo -[3,2-a]-S-triazine-5-7-thiones (xx).and found antibacterial
agents.In compound (xx),
R
Cl
N
N
N
X
N
S
Cl
XX
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d).Pawar et al have synthesized 6-hydroxy-3-methyl-1-phenylpyrazolo [5,4-d] pyrimidine. (xxi), found antibacterial agents.
H C
3
CH = N
N=CH
CH3
N
N
N
CI
N
IC
H
R
xxi
e).Novinson et al have synthesized substituted triazolo-pyrimidine derivatives and found antibacterial actvity.In compound (xxii), R=
pyridyl
CH3
N
N
N
N
R
CH3
XXII
f).Lewis et al have synthesized 3-substituted pyrido [3,4-e]-as-triazine(xxiii)&(xxiv) and found antibacterial useful agents.
N
N
N
N
CH3
XXIII
H
N
NH
N
N
CH3
XXIV
g).Saeki et al have synthesized triazine derivatives (xxv), where R=alkyl,Ph. and found antibacterial useful agents.
RO C
O
N
O
CO R
2
2
N
N
O
CO R
2
xxv
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4
.Anticonvulsant :These are defined as the agents that prevents the severity of convulsive seizures.
a).Kreutzberger et al have synthesized 2,4-dichloro-6dialkylamino-1,3,5- triazine derivatives(xxvi)and found anticonvulsant useful agent
N-(CH -CH=CH )
2
2 2
N
N
Cl
N
Cl
(xxvi)
b).Chapleo et al have synthesized some substituted-1,3,4- thia/ oxadiazoles (xxvii). ) and found anticonvulsant useful
agent.X=O,S,R=H,Me,R
1
=R
2
=H,alkyl,Ph-CH2.
CF3
R NR1
X
N-C-NHR2
N
N
(xxvii).
c).Waetzen et al have synthesized oxadiazolyl imidazobenzodiazepines (xxviii) which has useful anticonculsant activity in mice. In
compound (xxviii) X=Br, Cl ,F, Me, CF3 ,CN.
N
N
N
O
N
N
Me
X
O
(
xxviii).
5
.Antiallergic:A number of heterocyclic compounds have shown the antiallergic activity.
a).Musser et al have synthesized 2-(2, 3-dihydro-2-oxo-1, 3 ,4-oxadiazol-5-yl) benzoheterocycles (xxix), (xxx). In compound xxix X=O,
2
NMe, CCl, CH, CMe; X'=N, S, CH
2
, NH; R=H, Ac, CO
2
Et, Me etc. R'=H, 5-Cl', 5-(CO
CO ET
2
Me), 5-CO
2
Et and in compound xxx R =H,
2
R1
X
O
X
O
X
X1
CONHNHR2
N
NR
(xxix)
(xxx)
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b).Khandwala et al have synthesized 1-menthyl-2-[1,3,4-oxadiazol-2(3H)-one-5-yl] benzimidazole(xxxi)and related compounds as
antiallergic agents.
Me
N
O
O
N
N
NH
(xxxi)
6
. HERBICIDAL ACTIVITY
These are the drugs which destroy the unwanted plants alongwith some grasses without affecting the food
crops. Some substituted Oxadiazoles , triazines and condensed heterocyclic systems posses this activity.
a). Brouwer, et al have synthesized oxazole and Oxadiazole benzoic acid derivatives (xxxii &xxxiii) as herbicides. In compound xxiii
2
2
R'=H, R =H, Me; R'=Et, Bu; R =H and in compound XXIV r=Ph, substituted phenyl, (3-pyridyl),Me, R'=H, Me, Et, Propy, Butyl, Octyl,
Dodecyl.
1
R1
CO R
2
R2
CO
2
N
N
N
Ph
O
R
O
xxxii
xxxiii
b). Rorer and coworkers have synthesised phenyl-2-[3-methyl-1,3,4-oxdiazol-2-(3H)-one] sulfonyl pyrimidyl urea (xxxiv)
.
N
N
-Me
OMe
O
O
N
N
SO2NHCONH
OMe
xxxiv
c). Bandarenko et al have synthesised –s-triazines (xxxv), a new series of biologically active compounds. In these compounds R, R1,
MeO,-NH , NMe ,NHCHMe , SH, Sme, SEt.. Some of these shows herbicidal activity.
R
2
= Cl,
2
2
2
R
N
R1
N
N
R2
xxxv
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1
d). Two well known herbicides such as simazine (xxxvi) R=R = ethyl and atrazine R=ethyl; R1=isopropyl are persistent soil acting
herbicides which can be applied n large concentration (5-10/ha) as total weed killer.
Cl
N
N
RHN
N
NHR1
xxxvi
e). Westerman et al have prepared 6,7-dihydro-1,3,4-triazolo[ 1,5-a ]-1,3,5-triazin-2-Sulfonamides (xxxvii) and found them as agents with
herbicidal and plant growth regulting activity. In compound xxxvii Ar=(un) / substituted Ph, naphthyl, pyridyl; R=H, acyl, alkyl,phenyl-
alkyl,(un) substituted carbonyl etc.R
1
,R
2
= phenyl; X=O,S.
X
N
N
NR1
N
N
R2
ArNSO2
xxxvii
Anticancer activity
Anticancer refers to a group of disease caused by several agents like as chemical compound, radiant energy.
Cancer is characterized by an abnormal & uncontrolled division of cell exhibiting varying degree of
malignancy which produce tumor & invade adjacent normal tissue. These agents are used for treatment of
cancer or either kill cancer cells or modify their growth.
a).Stanton HLK, et al have synthesized (xxxviii) benzothiazole containing phthalimide and studied their anti-cancer activity on human
carcinoma cell lines
O
N
S
O
OCF3
(
xxxviii)
b).Wang M et al have(xxxix) synthesized carbon 11 labeled fluorinated2-aryl benzothiazoles used for protein emission tomography(PET) to
image tyrocinekinese in cancer
OCH3
N
OCH3
S
OCH3
(
xxxix)
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c) Aboraia S. Ahmed et al have synthesized 3-acetyl-2-substituted phenyl -5-(3,4,5-trimethoxyphenyl)-2,3-dihydro-1,3,4-oxadiazole
derivatives and these compound were screened for their in vitro antitumor activities against PC3, BGC823, & Bcap-37 by MTT method
O
CH3
H CO
3
N
N
H CO
3
O
R
H CO
3
(
xxxx)
d). Jin Jiang Chen et al have synthesized a new series of 5-(2-hydroxyphenyl)-2-substituted -2,3-dihydro-1,3,4- oxadiazole-2-thione
derivatives The promising anticancer activities were reported.
Cl
NH
N
N
O
S
OH
(
xxxxi)
e).Sączewski F et al have Synthesized(xxxxii) and (xxxxiii) and reported anticancer activity of novel 2,4-diamino-1,3,5-triazine derivatives
and of novel alkenyl -1,3,5-triazine derivatives, it showed growth inhibitory activity in low micromolar concentrations against renal cancer
A498 cell line and colon cancer cell line COLO 205.
H
H
C
CN
N
N
N
N(CH3)2
C
H
C
N
N
N
R
NH2
R
N
NH
2
(
xxxxiii)
(xxxxii)
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