355
A CONCISE CHEMICAL AND BIOLOGICAL POTENTIAL OF THIADIAZOLE ANALOGUES
Mohammad Asif
Department of Pharmacy, GRD (PG) Institute of Management and Technology, Dehradun, 248009, India
*Corresponding author. E-mail : aasif321@gmail.com Tel.: Phone: +91 9897088910
Recieved 29 August 2014, Revised 20 September 2014, Accepted 28 September 2014.
Abstract
The thiadiazole is one of the most important and well-known five-membered heterocyclic nuclei, which is a common and integral feature of a variety of natural products and medicinal agents. Thiadiazole nucleus is present as a core structural component in an array of drug categories such as antimicrobial, anti-inflammatory, analgesic, antiepileptic, antiviral, antineoplastic, and antitubercular agents. The activity of thiadiazole derivatives has established them as pharmacologically significant scaffolds. The structural modifications of thiadiazole rings with different atoms or groups cause various pharmacological activities. Chemical properties of 1,3,4-thiadiazole have been reviewed in the last few years. However, the usefulness of 1,3,4- thiadiazole as a privileged system in medicinal chemistry has prompted the advances on the therapeutic potential of this system. This review provides a brief summary of the medicinal chemistry of 1,3,4-thiadiazole system and highlights some examples of 1,3,4-thiadiazole- containing drug substances in the current literature. A survey of representative literature procedures for the preparation of 1,3,4-thiadiazole is presented in sections by generalized synthetic methods
Keywords: Heterocyclic compound, thiadiazole, chemistry, biological activities, synthesis.
356
1. Introduction
Heterocyclic compounds are attractive to medicinal chemists because of their unique chemical properties and wide-ranging biological activities. Despite significant research progress on heterocyclic ring systems, efforts are ongoing to identify novel heterocyclic compounds with potent bioactivities. Many compounds containing a five-membered heterocyclic ring display exceptional chemical and biological activities. Five-membered heterocycle compounds, thiadiazoles are common and typically possess biological activities. The thiadiazole ring has been used to link compounds such as antiparasitic and antimicrobial agents in the past, and some of the resultant drugs are still in clinical use [1-4]. The thiadiazole ring is an important framework with broad-spectrum biological activity. Thiadiazoles have therapeutic potential, highlighting the versatility of this scaffold in medicinal chemistry. The unique properties of thiadiazoles are also discussed in relation to their potential effect on activity. The sulfur atom of the thiadiazole imparts improved liposolubility, and the mesoionic nature of thiadiazoles makes these compounds better able to cross cellular membranes. The thiadiazole-containing compounds, to their synthesis and diverse biological activities, such as anti-inflammatory, anticancer, antibacterial, antifungal, antiviral, antiparasitic, anticonvulsant, anticoagulant, antidiabetic, anti-Helicobacter pylori, leishmanicidal and to show the significant utility of the thiadiazole scaffolds in medicinal chemistry [5-9]. The molecular target of 1,3,4-thiadiazoles includes the following enzymes: carbonic anhydrase, cyclooxygenase, neutral endopeptidase, aminopeptidase N, matrix metalloproteinases, phosphodiesterases and tyrosine kinase [10-13].
There are four types of thiadiazole: 1,3,4-, 1,2,4-, 1,2,5- and 1,2,3-thiadiazole (Figure 1 a), the most fully investigated of these being the 1,2,4- and 1,3,4-thiadiazoles. It has been widely reported that compounds bearing thiadiazole rings exhibit different types of pharmacological activities [14]. A number of thiadiazole-containing drugs are currently on the market:
acetazolamide and methazolamide are diuretics, acting through inhibition of carbonic anhydrase;
their derivatives display additional activities, including anticonvulsant and selective cerebral vasodilation, as well as the anticipated inhibition of carbonic anhydrase [15,16]. Other thiadiazolecontaining drugs include, cefazolin sodium and cefazedone-first generation cephalosporins; timolol-a nonselective b-adrenergic receptor blocker used for the treatment of hypertension, angina, tachycardia and glaucoma; xanomeline-a selective agonist of muscarinic acetylcholine receptor subtypes M1 and M4; and megazol-an antiparasitic drug.
357 N N
S S
O NH2
O HN
H3C O
Acetazolamide
N N S
S O
NH2 O H3C N
O H3C
Methazolamide N S N
N O
HN O
HO CH3
CH3 CH3
Timolol
N N S CH3 S
S N HN
O N O
Cl
Cl O
HO O
Cef azolin
N N S
O CH3
N
H3C Xanomeline
N N S CH3
S S
N HN
O N
HO O O
N N N
Cefazedone
N S N N
N CH3
O2N NH2
Megazol
1,3,4-Thiadiazoles are mesoionic-a poly-heteroatomic system containing a five-membered heterocyclic ring associated with conjugated p and p electrons and distinct regions of positive and negative charges [17,18]. Mesoionic systems are dense and highly polarizable, with a net neutral electron Many compounds containing a five-membered heterocyclic ring display exceptional chemical properties and versatile biological activities. The thiadiazoles are summarized according to their therapeutic potential, highlighting the versatility of this scaffold in medicinal chemistry. The unique properties of thiadiazoles are also discussed in relation to their potential effect on activity. Thiadiazole is a bioisostere of pyrimidine and oxadiazole, and given the prevalence of pyrimidine in nature it is unsurprising that thiadiazoles exhibit significant therapeutic potential. The sulfur atom of the thiadiazole imparts improved liposolubility, and the mesoionic nature of thiadiazoles makes these compounds better able to cross cellular membranes. The thiadiazoles, a brief introduction to their synthesis and diverse biological activities and to show the significant utility of the thiadiazole scaffolds in medicinal chemistry [19].
The 1,3,4-thiadiazole moiety have been widely used by the medicinal chemist in the past to explore its biological activities. The Development of 1,3,4-Thiadiazole Chemistry is linked to the discovery of Phenylhydrazines and hydrazine in the late nineteenth century. The first 1,3,4- Thiadiazole was described by Fischer in 1882 but the nature of the ring system was confirmed first in 1890 by Freund and Kuh. There are several isomers of thiadiazole, that is 1,2,3
358 Thiadiazole, 1,2,5 Thiadiazole, 1,2,4 Thiadiazole and 1,3,4 Thiadiazole. 1,3,4 Thiadiazole is the isomer of thiadiazole series. A glance at the standard reference works shows that more studies have been carried out on the 1,3,4 Thiadiazole than all the other isomers combined. Members of this ring system have found their way in to such diverse applications as pharmaceuticals, oxidation inhibitors, cyanide dyes, metal complexing agents. The ending -azole designates a five membered ring system with two or more heteroatoms, one of which is Nitrogen. The ending –ole is used for other five membered heterocyclic ring without Nitrogen. The numbering of monocyclic azole system begins with the heteroatom that is in the highest group in the periodic table and with the element of lowest atomic weight in that group. Hence the numbering of 1,3,4 Thiadiazoleis done in following manner. This designates that one sulphur group is present in the ring.
S N N
1,2,4-thiadiazole
N or
S
N N N
S1 2 4 3
5
1,3,4-thiadiazole
S N N
1,2,3-thiadiazole
N S N
1,2,4-thiadiazole Figure 1. a) Core structures of thiadiazoles.
Fused systems containing the thiadiazole ring also give rise to compounds with varied bioactivities, such as anticancer [20-22], anticonvulsant [23], antimicrobial [9,24], antitubercular [25-27] and antiviral [28] properties. Although thiadiazoles have advantages over other commonly found therapeutic scaffolds, their toxicity should not be underestimated. Through discussing this scaffold according to the associated biological activity and therapeutic application, this review aims to demonstrate the potential of thiadiazole rings in medicinal chemistry.
2. Synthesis
Different synthetic methods can be employed for the preparation of thiadiazole rings. Generally, 1,2,4-thiadiazoles can be synthesized from carboxylic acid and reagents containing N’- mercaptoformimidamide through condensation and dehydrative cyclization. 1,2,4-Thiadiazoles with the same groups in the 3- and 5-positions can be obtained by oxidation of the corresponding thioamide. 3-Chloro-1,2,4-thiadiazole, an important intermediate, can be synthesized by the appropriate amidine and trichloromethyl hypochlorothioite (fig 2a). 1,3,4-Thiadiazoles can be prepared using Lawesson’s reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-
359 dithione) after the condensation of a carboxylic acid and hydrazide (fig 2b). They also can be obtained by the reaction of 1,3,4-oxadiazoles and phosphorus pentasulfide. The 1,3,4-thiadiazole ring can be generated by the cyclization of N’-((dimethylamino)methylene)-N,N- dimethylformohydrazonamide and hydrogen sulfide. 1,2,3-Thiadiazoles can be made by reaction of 1,2-substituted-ethanone and 4-methylbenzene sulfono hydrazide [29]. 4-Carboxyl-1,2,3- thiadiazole can be prepared from (E)-2-(2-(ethoxycarbonyl) hydrazono) propanoic acid and thionyl chioride (fig 2c). Finally, the 1,2,5-thiadiazole ring can be synthesized by the oxidative cyclization of ethane-1,2-diamine. 3-Chloro-4-substituted-1,2,5-thiadiazole can be obtained by the cyclization of disulfur dichloride and 2-amino-2-substituted-acetonitrile, which can be made from aldehydes [30]. The condensation reaction of 1,2-diketones and SO2(NH2)2 produces 1,2,5- thiadiazole-1,1-dioxides (fig 2d).
A) 1,2,4-thiadiazole (1)
R1 OH O
R2 N
NH2 HS
+ a O
S N H2N
R1
R2
b N
S N R1
R2
1
NH2 R
N S
N R
R S
c
1
NH2
R N
S N R
Cl NH2+Cl-
d
1
A) 1,2,4-thiadiazole: a) Carbonyldiimidazole (CDI), DMF; b) CDI, DMF, D; c) I2, C2H5OH; d) CCl3SCl, NaOH, CH2Cl2. 88C; R=R1= R2= alkyl or aryl
B) 1,3,4-thiadiazole (2)
R1 OH O
R2 N H
R1 N H
O HN
N S
O O N
R2 R1 R2 NH2
+ e
f
2 R=R1= R2= alkyl or aryl
N O
N N
S
g N
H3C N
H3C N N N
S
h N N
CH3 CH3
2 B) 1,3,4-thiadiazole: e) 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), hydroxyl benzotriazole (HOBt),s THF, RT; f) Lawesson’s reagent, THF, reflux; g) P4S10, xylene, D; h) H2S, CH=OH, RT;
360 C) 1,2,3-thiadiazole (3)
O
R2 R1 H3C
NH NH2
O S O
+
S N N
R2
R1
i
3 R=R1= R2= alkyl or aryl
CH3 NH N
S N N
j
O HO
O
CH3
OH O
C) 1,2,3-thiadiazole: i) 1. EtOH, reflux, 3 h; 2 SOCl2, CHCl3, 0–5°C, 4 h; j) SOCl2, 60°C;
D) 1,2,5-thiadiazole (4)
NH2
H2N N
S
k N
4 H
R1
N S O N
R1 CN OH
R1 CN NH2
m n
l
R1 4 Cl
O O
+ H2N S O
O NH2
o
N S N
O O R1= alkyl or aryl
D) 1,2,5-thiadiazole: k) S2Cl2, DMF, 80°C; l) KCN/H2O/CH3COOH; m) NH4Cl/NH3 (aq); n) S2Cl2/DMF; o) HCl, C2H5OH, RT.
Scheme 1. Synthesis of various thiadiazoles
1,2,3 Thiadiazole 1,2,5 Thiadiazole 1,2,4 Thiadiazole 1,3,4 Thiadiazole
1,3,4-Thiadiazole: There has been intense investigation of different classes of thiadiazole compounds, many of which known to possess interesting biological properties such as antimicrobial [31,32], antituberculosis, anti-inflammatory [33], anticonvulsants [34], antihypertensive, antioxidant [35], anticancer [36,37] and antifungal [38] activity.
2.1. Recent Strategies in the Synthesis of 1,3,4-thiadiazoles:
Recent strategies on the synthesis of 1,3,4-Thiadiazole derivatives can be summarized in to following points;
361 (a) From Thiosemicarbazides: Many synthesis of the 1,3,4-Thiadiazole proceed from thiosemicarbazide or substituted thiosemicarbazide.
Method 1.
Thiosemicarbazide (6) has cyclizes directly to 2-amino-5-methyl-1,3,4-thiadiazole (7) with acetyl chloride (5). This simple route to 2-amino 5-substituted-1,3,4-thiadiazole seems to be quite general (R=methyl), norhydnocarpyl, benzyl, cyclopropyl and many others.
5 6 7
R Cl O
+
H2N N H S
NH2
N N S
NH2 R
The acetyl chloride (5) could bring about the cyclization of alkyl- or arylsubstituted thiosemicarbazide. For example, the action of acetyl chloride on 4-methyl thiosemicarbazide (8) produces 5-methyl-2-methylamino-1,3,4-thiadiazole (9).
H3C Cl O
+
HN N H S
CH3 N N
S
NH H3C
H2N
CH3
8 9
Method 2:
A number of 2-amino-5-aryl-1,3,4-thiadiazole using phosphoric acid as the dehydrating agents.
An example of smooth cyclization in high yield by phosphoric acid is the formation of 2- benzamido-5-phenyl-1,3,4-thiadiazole (11) from 1,4-dibenzoylthiosemicarbazide (10).
HN
NH NH O
O
O N
N S
N H
H3PO4 O
10 11
Method 3:
Formic acid could cyclize the alkanoyl halides by acylation. He found that by heating 4- phenylthiosemicarbazide (12) with formic acid, 2-anilino-1,3,4-thiadiazole (13) was formed.
362 NH N
H S
H2N
+
H OH O
N N
S NH
12 13
Method 4:
A useful preparative method for 2-amino-5-mercapto-1,3,4-thiadiazole (6) was developed. When thiosemicarbazide is treated with carbon disulphide and potassium hydroxide, the potassium salt of thiosemicarbazide-4-dithiocarboxylic acid (14) is formed. Heating this potassium salt of thiosemicarbazide-4-dithiocarboxylic acid (14) to 140°C causes cyclization to the salt of 2- amino-5-mercapto-1,3,4-thiadiazole (15).
NH NH2 S
H2N
+
CS2 KOHS K
NH S
HN
NH2 S 140o
N N S S K
NH2
14 15 6
In certain instances neutral carbon disulphide reacts directly with thiosemicarbazide to form amino mercaptothiadiazoles. A modification of the carbon disulphide-thiosemicarbazide procedure which results in higher yield of 2-amino-5-marcapto-1,3,4-thiadiazole is carried out in dimethylformamide at 80°, the yield is over 90%.
Method 5:
The benzalthiosemicarbazones (16) could be oxidatively cyclize to form 2-amino-5-phenyl- 1,3,4-thiadiazole (17) by ferric chloride. A large number of 5-substituted 2-amino-1,3,4- thiadiazole have been prepared.
NH NH2 S N
N N S NH2
FeCl3
16 17
NH NH S N
N N
S H
FeCl3 N
CH3
CH3
18 19
A number of aldose thiosemicarbazones could be converted to thiadiazole derivatives.
363 (b) From Thiocarbazides: There are two method by which 1,3,4-thiadiazole can be prepared from thiocarbazides.s
Method 1:
If 1-phenylthiocarbazide (20) is heated with formic acid, it is converted to 2-phenylhydrazino- 1,3,4-thiadiazole (21).
H2N NH
S NH
HN N
N S
N H
HN
HCOOH
20 21
Method 2:
This method is related to the oxidation of 1-phenylbenzalthiocarbazone (22) to 2-phenyl-5- phenyl hyrazino-1,3,4-thiadiazole (23).
N NH
S NH
H N
HCOOH HN N
H N
N S
NH H N
22 23
(c) From Dithiocarbazates: Following methods have been reported for the preparation of 1,3,4- thiadiazole from dithiocarbazates.
Method 1:
Another route to 1,3,4-thiadiazole is via substituted dithiocarbazic acid and their esters. A reaction which belongs in this group is the formation of 2,5-dimercapto-1,3,4-thiadiazole (25) by action of carbon disulphide on hydrazine (24) in basic medium.
H2N NH2+ 2CS2 OH-
N N S
SH HS
24 25
Method 2:
When 3-acyldithiocarbazic esters (26,28) are treated with acids, they cyclize to form substituted thiadiazoles (27,29). This is a quite general reaction. Both benzyl and methyl 3- acyldithiocarbazates have been employed.
364 H3C N
H S HN S O
H+
N N S S
CH3
26 27
H2N S HN S
N N S S
CF3
(CF3CO)2O
28 29
(d) From Thioacylhydrazines: Thioacylhydrazines may often serves as starting materials for the preparation of 1,3,4-thiadiazole. If thiobenzoylhydrazine (30) is heated with ethyl ortho formate (31), 2-phenyl-1,3,4-thiadiazole (32) is formed. If ethyl orthoacetate is substituted for the orthoformate, 2-methyl-5-phenyl-1,3,4-thiadiazole is obtained.
S NH H2N
O O
O
CH3
CH3 H3C
N
N S
+
30 31 32
Thiobezhydrazide is smoothly converted to 2-phenyl-1,3,4-thiadiazole by the action of formic acid. Thiobenzhydrazide is reported to form 2,5-diphenyl-1,3,4-thiadiazole (33) in small amount when warmed in benzene.
S
HN NH2 N N
S
30 33
(e) From Acylhydrazines: The 2,5-diphenylthiadiazole (36) by a variety of methods. He found that benzoylhydrazine (34) or N,N’-dibenzoylhydrazines (35) react with phosphorus pentasulfide to form 2,5-diphenyl-1, 3, 4-thiadiazole (36).
365 HN
NH O
O
HN NH S
S
NH2 NH O
P2S5
NH2 NH S
P2S5
N N S
35
34 36
The reaction of N, N’-diacylhydrazine (37) with phosphorus pentasulfide was used by Stolle and his students for the preparation of a large number of 2,5-disubstituted-1,3,4-thiadiazole (38).
H3C N
H CH3 H N
N N H3C S
CH3 O O
P2S5
37 38
(f) From Bithioureas: Bithiourea and substituted bithiourease have been converted to 1,3,4- thiadiazole by several methods.
Method 1:
Bithiourea (39), when treated with 3% hydrogen peroxide is cyclized to 2,5-diamino-1,3,4- Thiadiazole (40).
H3C N
H CH3
HN
N N H2N S
NH2 S S
H2O2
39 40
Method 2:
Acetic anhydride acts on bi-thiourea to form a diacetyl derivative of 2,5-diamino-1,3,4- Thiadiazole. The acetyl group is easily removed by hydrolysis to give the parent thiadiazole.
3. Reactivity of the 1, 3, 4-thiadiazoles:
(A) Rearrangements and Ring Opening Reaction:
The 1,3,4-thiadiazole ring is rather susceptible to attack by strong neucleophile. Thus the parent compound is stable to acids but is readily cleaved by bases. 2-Amino- and 2-hydrazino-1,3,4-
366 thiadiazole can be rearranged to 1,2,4-triazoline-3(2)-thiones. The 2-amino- and 2-methylamino- 1,3,4-thiadiazole (41, R=H and CH3) are rearranged by methylamine in methanol at 150o to the isomeric triazolinethiones (42).
N S N
NH R
HN N
SC R
41 42
2-Amino 1,3,4-thiadiazole (7, R=H), when refluxed with benzyl amine in xylene, gave a mixture of about equal amount of 2-benzylamino-1,3,4-thiadiazole (41, R = CH2Ph) and 4-benzyl-1,2,4- triazolin-3(2)-thione (42, R=CH2Ph). The same two compounds were formed in the reaction between 2-chloro-1,3,4-thiadiazole and benzyl amine (43).
N S
N
R NH2
N S
N
R Cl NH2
NH2 +
+
7 44
43 44
N
S N
NH R
+
N NH N
CS R
41 42
Similarly, 2-alkyl-5-chloro-1,3,4-thiadiazole (45) reacted with a large excess of hydrazine hydrate on heating to give 4-amino-1,2,4-triazolin 4-amino-1,2,4-triazolin-3(2)-thiones (46).
N S
N
R Cl+H2N NH2
N N
CS H N R
NH2
45 46
Under the same conditions, 2-amino-5-chloro-1,3,4-thiadiazole (47) and 2-amino-1,3,4- thiadiazolin-5(4)-thione (48) gave a mixture of 3,4-diamino-1,2,4-triazoline-5(1)-thione (49) and 3-hydrazino-4-amino-1,2,4-triazoline-5(1)-thione (50). 2,5-Dichloro- and “2,5-dimercapto-1,3,4- thiadiazole” gave only (50).
N S
N NH2
Cl +H2N NH2
N N
CS HN
H2N
NH2 N
S CS NH
H2N +H2N NH2
N N
CS HN
HN
NH2 NH2
47 +
48
49 50
367 Similar rearrangements can be affected by acids. When 1-benzyl-1-(1,3,4-thiadiazole-2-yl) hydrazine (51) was refluxed with dilute hydrochloric acid, the triazolinethion (52, R=H) was formed in quantitative yield. When the reaction was performed in the presence of some acetic acid, a mixture of (52) (R=H) and (52) (R=CH3) was formed.
S N N R
N H2N
N CS N H
H2N
N CS N H3C
H2N
+
Dil HCl
51 52 53
In this acid catalyzed rearrangement 2-benzylthiocarbohydrazide (53) is likely an intermediate.
The rearrangement of (7) by benzyl amine probably proceeds with ring opening to an amidrazone (54) followed by recyclization to (42) (R=CH2Ph).
N S
N NH2
R HN
HN
N C
S
NH2 N
N CS HN
R=H
7 Amidrazone (54) 42
3.1. Substitution Reaction:
Although the 1,3,4-thiadiazole ring is classed as π-excessive, the presence of two nitrogen atoms of pyridine type in the ring leaves the carbon atoms with rather low electron density, and consequently no electrophilic substitution in the unsubstituted 1,3,4-thiadiazole ring have been recorded. A bromine adduct of the simple 1,3,4-thiadiazole, but it decomposed and lost bromine in the air. Nitration, even under drastic condition could not be achieved. The 2-phenyl-1,3,4- thiadiazole to a mixture of concentrated nitric acid and sulphuric acid at 0o and obtained a mixture of the three isomeric 2-nitrophenyl-1,3,4-thiadiazole in the ratio p: m:o=2:3:1, but no 2- phenyl-5-nitro-1,3,4-thiadiazole. A 2-amino group does activate the ring towards electrophilic agents, could prepare 2-amino-5-bromo-1,3,4-thiadiazoleby bromination of 2-amino-1,3,4-
368 thiadiazole in 40% hydro bromic acid. The product was not isolated but was diazotized to give 2,5-dibromo-1,3,4-thiadiazole [39].
4. Physical properties of -1, 3, 4-thiadiazoles:
4.1. Structure and Aromatic Properties
A careful analysis of the microwave spectra of 1,3,4-thiadiazole and three isotopically substituted species. They could determine the structure of the molecule with an uncertainty of 0.03 A° in the coordinates of the hydrogen atom and of less than 0.003 A° in the coordinates of the other atoms. By an analysis of difference between the measured bond lengths and covalent radii, the author came to the conclusion that the aromatic character, as measured by the π- electron delocalization decreases in the order –1,2,5-thiadiazole > thiophene > 1,3 4-thiadiazole
> 1,2,5-oxadiazole.
4.2. Dipole Moment
Dipole moment of 1,3,4-thiadiazole in the gas phase was found a value of 3.28+-0.03 D. The π- electron distribution and the bond moment, a dipole moment of 3.0 D can be calculated, directed from the sulphur atom towards the center of the nitrogen-nitrogen bond.
5. Discussion
Our results showed that, electrophilic substitution of phenyl ring is beneficial for antinociceptive activity. Therefore, it is possible that replacement of these kinds of aryl groups with a thiadiazole structure has changed the mechanism of enzyme-receptor interaction and highlighted the importance of aryl rings substituent. Since in vivo activity depends on highly complex physiological interactions, at this moment we are unable to rationalise all of these pharmacological results. Therefore, our initial screening results demonstrated that the presence of electrophilic substituted phenyl group on 1,3,4-thiadiazole ring might contribute to their analgesic activity. Further studies using these compounds might be useful to develop better candidates with potent analgesic activity. Stimulated by these findings, our attention has been focused on the synthesis of a series of new thiadiazole derivatives, which are expected to show various types of therapeutic activities. There are numbers of five member heterocycles containing nitrogen and sulphur atom, have treatment to be potential chemotherapeutics and parmacotherapeutics agents. The biological profile of thiadiazoles is very extensive. It is well
369 documented that 1,2,3-thiadiazoles undergo multiple transformations into a wide variety of products like, antitubercular [40], anticancer [41], anthelmintic [42], anti-inflammatory [32] and antimicrobial, antiviral [41,43], antifungal activities etc. On the other hand, a considerable number of 1,3,4-thiadiazole derivatives endowed with antimicrobial property have been reported [44-46]. 1,3,4-Thiadiazoles represent an important heterocyclic system due to their pharmacological activity. They were found to have antihypertensive, anticonvulsive activities, antimicrobial, and biological activities, also some 1,3,4-thiadiazole have industrial importance, act as semiconductors. As a part of a program directed for developing new biologically active compounds, it is reported here on the utility of hydrazonoyl halides as a candidates for a facile synthetic route to substituted 1,3,4 thiadiazoles. The development of resistance to current antibacterial therapy continues to drive the search for more effective agents. In addition, primary and opportunistic microbial infections continue to increase the number of immunocompromised patients, those suffering from such as AIDS or cancer or who have undergone organ transplantation. We designed and prepared a series of thiadiazole in an effort to investigate their antimicrobial activities. These above observations promoted us to synthesis of the title compounds for various types of biological activities. Results revealed that synthesized thiadiazole derivatives exerted effects against various disorders. Further research is expected to boost the use of thiadiazole in the nearby future against diseases. The biological profile of thiadiazoles is very extensive [47]. 1,3,4-thiadiazole derivatives are associated with diverse biological activities probably by virtue of toxophoric -N=C-S- grouping. The reported biological activities of 1,3,4-thiadiazoles include antiinflammatory, antiviral, leishmenicidal, adenosine receptor antagonist, diuretic activity, antihypertensive, anthelmintic, antifungal, antimicrobial and analgesic activity. Many substituted 1,3,4-thiadiazole derivatives were developed [48-50].
The synthesis and studies on the analgesic properties of compounds containing substituted 1,3,4- thiadiazoles have been described previously [51-55]. Some evidences have suggested that the hydrazone moiety present in the derivative possesses different pharmacophoric characters for their pharmacological effects [56-60].
6. Conclusion
The 1,3,4-, 1,2,4-, 1,2,5- and 1,2,3-Thiadiazoles were shown to be present in compounds with diverse activities, such as anti-inflammatory, anticancer, antibacterial, antifungal, antiviral, antiparasitic, anticonvulsant, anticoagulant, antidiabetic and so on. Based on the activities of the
370 thiadiazole-containing compounds summarized here, we can conclude that the thiadiazole scaffolds have significant utility in the development of therapeutically relevant and biologically active compounds. The thiadiazole ring possesses similar chemical properties to the pyrimidine ring, and can be considered a bioisostere. The chemistry of thiadiazoles is well known. The cyclization of suitable open-chain organic molecules is a classical and common approach to the synthesis of various disubstituted thiadiazoles. They are widely known as compounds with various kinds of biological activities showing anticancer, diuretic, antitubercular, anti- Helicobacter pylori and leishmanicidal agents. Many of them influence on exhibiting antidepressant, analgesic and anxiolytic effects. The synthesis of 1,3,4-thiadiazole heterocycles that have been reported to date illustrates different approaches to the challenge of preparing these bioactive products and allows the synthesis of many novel chemical derivatives. In general, 1,3,4-thiadiazole derivatives are prepared by appropriate rearrangements, ring opening and substitution reaction. The area of the synthesis of 1,3,4-thiadiazole rings continues to grow, and the organic chemistry will provide more and better methods for the synthesis of this interesting heterocycle, allowing the discovery of new drug candidates more active, more specific and safer.
Acknowledgement: The authors are thankful to GRD (PG) IMT, Dehradun, India for providing technical support and facilities to carry out this work.
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