A Short Review on Biological Potential Thiopyridazine Analogues

Pyridazinone/thiopyridazinone derivatives represent one of the most active classes of compounds possessing a wide spectrum of biological activities such as cardiovascular properties, anti-inflammatory, analgesic, antidiabetic, antiviral, anticancer, antimicrobial, anticonvulsant and other biological activities. Some pyridazinthiones were tested for biological activities. Various pyridazinone/thiopyridazine derivatives were exhibited anticonvulsant activity against maximal electroshock seizure test, various pyridazine-thione derivatives were exhibited antitumor activity and some thiopyridazines were exhibited anti-microbial activity against various strains like Staphylococcus aureus, Escherichia coli, Bacillus subtillis and Candida albicans. Tricyclic ring system, pyridazino[6,1-b]quinazolin10-ones, benzimidazolo-pyridazine thione, and 1,2,4-benzotriazino-pyridazinethione along with imidazo-[1,2-b]pyridazinethione, 1,2,4-triazolo[4,3-b] pyridazine-thione derivatives were exhibited antimicrobial activity against gram-positive and gram negative bacteria as well as fungi.


Introduction
The review was carried out to discuss in detail about the substituted pyridazinone compounds. Heterocyclic compounds have been successfully used as antimicrobial, anticancer, antipyretic, hypoglycemic, antihypertensive, anti-tubercular, anti-inflammatory, analgesic, anti-viral and other useful agents. Various organo-sulfur compounds present in living and nonliving things. They occur in open chain, alicyclic, aromatic and heterocyclic compounds containing sulfur atoms or atoms as a part of chain/ring in the structure. In this review briefly study about the structure features and biological interest of thio-pyridazine derivatives and concluded that many researches had tested on thio-pyridazine derivatives having the biological activities. The chemistry of pyridazines and their fused heterocyclic derivatives has received considerable attention owing to their effective biological importance. Pyridazines have been reported to possess antimicrobial [1][2][3], antituberculosis [4][5][6], antifungal [7], anticancer [8], antihypertensive [9], herbicidal [10], anti-inflammatory [11] activities, and protein tyrosine phosphatase 1B inhibitors [12]. They also have an immense potential in agricultural science as plant growth regulators and crop protection agents [13]. The incorporation of two moieties increases biological activity of both and thus it was of value to synthesize new heterocyclic compounds having two moieties in the same molecules. Various derivatives of pyridazine incorporating other heterocyclic rings have been shown to display a wide spectrum in biological and therapeutic areas [14][15][16][17][18].
Pyridazine-thione (14) was used as a key intermediate for the preparation of numerous pyridazine derivatives such as 3,3'-(6,6-bis ( [22]. The action of phosphorus pentasulfide on the lactam function of pyridazin-3-ones, allowed us to obtain pyridazin-3-thiones, by reacting the sulfur atom with several reagents (alkyl halide, hydrazine  hydrate) [23][24][25]. The action of pentasulfide on ketones led to the thione function [26,27]. Thus the reaction conducted at reflux in pyridine on pyridazin-3-ones for 4 hours lead to pyridazin-3-thiones in good yields. The acute toxicity study showed that the synthesized derivatives are tolerated. Indeed, the limit dose of 1500 mg/kg i.p caused no lethality until 14 days. No effect was observed on groups of mice after oral administration at escalating doses. We deduce that the lethal dose 50 (LD 50 ) is probably more than 1500 mg/kg. The synthesized compounds 5(1'-benzylidène)-6-méthyl-(2H)-pyridazin-3-thione, 5(2'-chloro-1'-benzylidène)-6-méthyl-(2H)-pyridazin-3-thione, 5(4'méthoxy-1'benzylidène)-6-méthyl-(2H)-pyridazin-3-thione (31-33) were tested for antibacterial activity against certain pathogenic bacteria by disc diffusion method using both gram positive S. aureus, B. subtillis, gram negative E. coli and antifungal activity against C. albicans. Thus only the derivative 32 showed significant activity against S. aureus and E. coli. The presence of an electron attractor groups on the aromatic ring as chloro group is favorable for that activity. The derivative 33 containing the aromatic ring substituted by an electron donor by mesomeric effect (-OCH 3 ) inhibit the activity. In the case of C. albicans chloro group is not necessary, since the derivatives 31 and 32 have similar activity, however the (-OCH 3 ) group inhibits the activity. In conclusion, among the derivatives synthesized product 32 has a significant antimicrobial activity; in addition the acute toxicity study showed that this derivative has a low toxicity with a lethal dose 50 elevated [28] (Figure 3).
Various researches indicated that the presence of at least one aryl group, one or two electron donor atoms and/or an NH group in a special spatial arrangement is essential for antiepileptic activity. The presence of at least one aryl group, one or two electron donor atoms and/or an NH group in a special spatial arrangement seems to be necessary for antiepileptic activity. A study of anticonvulsant agents reveals that the presence of an amide moiety, cyclic or not, is present in most antiepileptic's. The pyridazinone ring system agrees with this salient feature and many papers have reported antiepileptic activities of pyridazine derivatives. Hence this feature of the ring system was tapped for the presence of any anticonvulsant activity [29,30]. A series of substituted 6-aryl-2,3,4,5-tetrahydro-3-pyridazinones (34a-e) and 6-aryl-2,3,4,5-tetrahydro-3-thio-pyridazinones (35a-e) were tested for their anticonvulsant activity. The substituted 6-aryl-tetrahydro-3pyridazonone (34a-e) followed by substitution with sulphur to yield the compounds (35a-35e). All the compounds 34a-e and 35a-e were tested for anticonvulsant activity by maximal electroshock-induced seizure (MES) test. The starting dose of the test compound was 10, 25, 50 and 100 mg/Kg and standard drug Phenytoin 25 mg/Kg. some compounds showed significant activity, rest compound were showed moderate anticonvulsant activity [31] (Figure 4).

Discussion
Because of the diversity in synthetic procedures, physiological and industrial significance, hetero cyclic chemistry has been and continues to be one of the most active areas of organic chemistry. As a result numerous heterocyclic compounds have been successfully used as antibacterial, anticancer, antipyretic, hypoglycemic, antihypertensive, antitubercular, anti-inflammatory and anti-HIV agents. In addition, they have also been used in agriculture, plastics, polymers, dyes and textiles. Hence heterocyclic chemistry still continues to draw the attention of synthetic organic chemists and is of great scientific interest. All large number of organo-sulfur compounds occur in living and non-living object. Organo-sulfur compounds lead to the fact that some of the compounds are useful in scientific and industrial growth. During the last three decades organo-sulfur chemistry developed at a much faster pace than any other branches of organic chemistry. The pyridazin derivatives are known for their therapeutic potential such as antihypertensive and cardio tonic, antifungal and other properties are also reported [32][33][34][35]. Pyridazines containing the group sulfur have important pharmacological activities.

Conclusion
Hetero cyclic chemistry has been and continues to be one of the most active areas of organic chemistry. As a result thio-pyridazine compounds have been successfully used as antibacterial, anticancer, anticonvulsant agents. Hence thio-pyridazine still continues to draw the attention of synthetic organic chemists and is of great scientific interest. Hence it can be concluded that many researches had investigated on thio-pyridazines having the biological activities.