The Pharmacological Importance of Some Diazine Containing ... · Diazines focus our attention because of their easy ﬁctionalization, which makes them attractive synthetic compounds

SOP TRANSACTIONS ON ORGANIC CHEMISTRYVolume 1, Number 1, August 2014

SOP TRANSACTIONS ON ORGANIC CHEMISTRY

The Pharmacological Importance of SomeDiazine Containing Drug MoleculesMohammad Asif*

Department of Pharmacy, GRD (PG) Institute of Management and Technology, Dehradun, 248009, India.*Corresponding author: [email protected]

Abstract:Two nitrogen atoms containing heterocyclic compounds or diazines, pyridazines, pyrimidines and

piperazines are important structural feature of many biologically active compounds and show

diverse pharmacological properties. These diazines hold considerable interest in the preparation

of organic intermediates and physiologically active compounds. Diazines focus our attention

because of their easy fictionalization, which makes them attractive synthetic compounds for

designing and development of the novel drugs in future. The potential biological activities of

diazines are cardiovascular, neurological, antimicrobial, anti-inflammatory, etc. Diazine is an

important lead owing to its inherent properties and therapeutic actions. Many of the successful

drugs are having diazine ring as pharmacophore.

Keywords:Biological activities; drugs; heterocyclic organic compounds; diazine; structural feature; cardio-

vascular disorders; neurological disorders

1. INTRODUCTION

The understanding the principles of drug design and developments of the synthetic drugs or molecules,it is necessary to understand the physicochemical properties of chemicals compounds used to developnew pharmacologically active compounds. The biological activities, mechanism of actions, metabolismand possible biological activities of the metabolites and importance of stereochemistry for moleculesfor new drug design. All these principles are based on the fundamental organic chemistry, physicalchemistry and biochemistry. Heterocyclic compounds contain besides, carbon, one or more atoms of otherelements, common hetero atoms are nitrogen, sulphur and oxygen. The heterocyclic compounds havinglesser common atoms such phosphorus, tin, boron, silicon, bromine, etc. have been much investigated inrecent years. The heterocyclic compounds having five or six atoms in the ring are the most important[1]. The practice of medicinal chemistry is devoted to the discovery and development of new agentsfor treating disease. The process of establishing a new drug is exceeding complex and involves talentof people from variety of disciplines [2]. An important aspect of medicinal chemistry has been toestablish a relationship between chemical structure and pharmacological activity [3]. Pyrimidine is asix membered cyclic compound containing 4 carbon and 2 nitrogen atoms and is pharmacologicallyinactive but its synthetic derivatives possess an important role in modern medicine [4]. Pyridazine

1


1, oxygenated derivative-pyridazinone 2 and benzfused pyridazine or phthalazine 3 are heterocycliccompounds that contain two adjacent nitrogen atoms (1,2-diazine) in the ring structure. They show awide range of pharmacological activities and are found in a lot of natural compounds having differentbiological activities [5–10].Many heterocyclic compounds derived from synthetic as well as naturalsources, commonly in practice contain one or more nitrogen in the heterocyclic ring system. Diazines(1,2-/1,3-/1,4-diazines) are important heterocylic rings. Recently, much attention has been focused ondiazine derivatives for their broad-spectrum biological activities. Various structural modifications werecarried out in diazines ring systems. These structural changes resulted in some fruitful biological activitiesof the diazine compounds [11–20].

A Psychological disorders are occurs in an individual and to cause distress or disability. The mentaldisorders have changed over time. Mental disorders can vary, may include dissociative disorders, mooddisorders, anxiety, psychosis, eating disorders, developmental disorders, personality disorders, ambulatorydisorders and many other. Mental disorders have been found to be common, with over a third of peopleat some point in their life. The central nervous sytem (CNS) is functionality far more complex thanany other system in the body so the drugs that act at CNS, it is difficult to understand its mechanismclearly. Nearly all the molecules entering the brain have to pass through the endothelial cell membranes,through the blood–brain barrier (BBB). It is more difficult for polar molecules to enter the brain unlessthey are actively transported. This factor must be taken when designing drugs to target the brain. Thelipid solubility increases the drug easily cross BBB and gives its response. The BBB also containsenzymes that protect the brain. Thus, this factor must be taken when designing drugs to target thebrain. Piperazine has chemical similarity with piperidine and readily absorbs water and carbon dioxidefrom the air. Various piperazine derivatives occur naturally. Piperazine exists as deliquescent crystalswith a saline taste. The Piperazine is a broad class of chemical compounds with important biologicalactivities [21, 22]. Most of these compounds can be classified as either phenyl/benzyl-piperazines,diphenylmethyl-piperazines (benzhydrylpiperazines), pyridinyl-piperazines, pyrimidinyl-piperazines, ortricyclics (piperazine ring attached to the heterocyclic ring via a side chain). Pipofezine (Azafen orAzaphen) is a tricyclic antidepressant (TCA) used as anti-depressant. Pipofezine is act as a potent reuptakeinhibitor of serotonin. It also has sedative as well as antihistamine activity.

Quinoxaline is nitrogen containing six membered heterocyclic, in which two nitrogen atoms are basedon pyrazine so called as benzopyrazine. Quinoxaline have become attractive target of extensive researchdue to its inherent properties and therapeutic uses. Quinoxaline finds many pharmacological activitieslike antimicrobial, antituberculer, anti-inflammatory, antihyper- glycemic, antitumor etc. Heterocycliccompounds are very widely distributed in nature and are particularly important because of the widevariety of physiological activities associated with this class of substances. Several of the importantcompounds contain heterocyclic rings, e.g. mostly the members of vitamin B complex, alkaloids,antibiotics, chlorophyll, other plants pigments, amino acids, dyes, drugs, enzymes, the genetic material,DNA etc [23]. Quinoxaline is also called as benzopyrazine. It is heterocyclic compound containingbenzene ring & pyrazine ring. Pyrazine are stable, colorless compound which are soluble in water.Diazines are fused to benzene ring to form quinoxaline. The pyrazine ring system is found in the fungalmetabolite aspergillic acid and in dihydro form in luciferin of several bettles including the fire fly is

2

The Pharmacological Importance of Some Diazine Containing Drug Molecules

Figure 1. Structures of six membered diazine compounds and its biological activities

3


responsible for the chemiluminescence of this ostracod. Methoxy pyrazine are very important componentof aroma of many fruits and vegetable such as Peas and Capsicum peppers and also of wines. NaturallyOccurring Pyrazine & Quinoxaline: Cyridina Luciferin Aspergillic acid Methoxy Pyrazine is used asFood Aroma. Cholenterazine: It is bioluminescent compound from a jellyfish and potential for use inbioassays.

2. BIOLOGICAL ACTIVITIES OF QUINOXALINE

antimicrobial activity: Antimicrobial agent shows activity against bacteria, fungi, mycobacteriumspecies, called antibacterial, antifungal, antituberculer activity respectively. There are various quinoxalinederivatives showing antimicrobial activity. Quinoxaline core antibiotics like Echinomycin, Triostin Ashowing antimicrobial activity by having DNA cleaving property. Design of quinoxaline antibiotics haveundertaken by several workers, but they posses limited application due to their toxic effect. It is believedthat the antimicrobial potency of the quinoxaline due to the facilitate approach of the structure to preventDNA directed RNA synthesis by virtue binding to CPG site on DNA.

Antimalarial: A new active compound from lead compound 3-(4’-chloro phenyl) quinoxaline-2-carbonitrile 1,4-di-N-oxide, which was subjected to a structural change in order to obtain new activecompounds: replacement of benzene in position 3 of the quinoxaline subunit by a heteroaromatic 5-member ring, 2-furane or 2-thiene. All these compounds were evaluated for antimalarial activity against P.falciparum. The 3-(2’-furyl) quinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives appear to be a noveland promising antimalarial candidates.

Anti cancer activity: Methyl (4-(substituted 2-quinoxalinyloxy) phenyl) acetates and ethyl N-{(4-(substituted 2-quinoxalinyloxy) phenyl) acetyl} glutamate analogs of methotrexate and evaluated for invitro anti cancer activity bioisosteric replacement of pteridine ring with 6(??)-trifluoromethyl quinoxalineaffords a good substrate for the classical antifolate analogs, and bioisosteric replacement of 2-NH groupwith an oxygen that in some cases was of relevance in anticancer activity. Quinoxalinebearing a 2-(4-substituted phenoxy) substituent were endowed with potent antitumor activity [24, 25].

Biological Importance of Pyrimidine: In medicinal chemistry pyrimidine derivatives have been verywell known for their therapeutic applications. The presence of a pyrimidine base in thymine, cytosineand uracil, which are the essential building blocks of nucleic acids, DNA and RNA is one of the possiblereasons for their activities [26]. Vitamins are essential for body. Pyrimidine ring is found in vitaminslike riboflavin, thiamine and folic acid [27]. Pyrimidine nucleus is also present in barbituric acid andits several derivatives e.g. Veranal) which are used as hypnotics. In addition to this, pyrimidine nucleusis also found in alloxan, which is known for its diabetogenic action in a number of animals. MedicinalImportance of Pyrimidine: In medicinal chemistry pyrimidine derivatives have been very well known fortheir therapeutic applications. Many pyrimidine derivatives have been developed as chemotherapeuticagents and are widely used.

Antimicrobial Activity: Microbes are causative agents for various types of disease like pneumonia,amoebiasis, typhoid, malaria, common cough and cold various infections and some severe diseases liketuberculosis, influenza, syphilis, and AIDS as well. Various approaches were made to check the roleof pyrimidine moiety as antimicrobial agent from the discovery of molecule to the present scenario.Hitchings, in 1948, made an important observation that a large number of 2, 4 di amino pyrimidines andsome 2-amino-4 hydroxy pyrimidines are antagonists of folic acid. These pyrimidines were than eventually

4


proved as inhibitors of the enzyme dihydrofolate reductase (DHFR). Amongst the 2,4-diaminopyrimidinedrugs, pyrimethamine is a selective inhibitor of the DHFR of malarial plasmodia. Trimethoprim, anantibacterial drug is also a selective inhibitor and selectively inhibits bacterial DHFR. Brodimoprim,is also found to be an effective antibacterial compound. Pyrimidine also shows antifungal properties.Flucytosine is a fluorinated pyrimidine used as nucleosidal anti fungal agent for the treatment of serioussystemic infections caused by susceptible strains of candida and Cryptococcus [28–34].

Anticancer Activity: The pyrimidine moiety with some substitution shows promising antitumor activityas there are large numbers of pyrimidine based antimetabolites. The structural modification may be onthe pyrimidine ring or on the pendant sugar groups. Early metabolite prepared was 5-fluorouracil, apyrimidine derivative followed by 5-Thiouracil which also exhibits some useful antineoplastic activities[35, 36]. Organic compounds and their complex with various ligands have found many applications inbiomedicine. Guanine nucleus containing antineoplastic compounds like mercaptopurine and tegafur etcwere discovered. Recently, new compounds have been developed like nimustine, uramustine, raltitrexedetc [37–44].

Analgesic and anti-inflammatory activity: Pyrimidine has a remarkable pharmacological efficiency andtherefore an intensive research has been focused on anti-inflammatory activity of pyrimidine nucleus. Newforms of thiamine are lipid-soluble like acetiamine, bentiamine etc., having therapeutic use in beriberi,polyneuritis, encephalopathy, pain, malnutrition and alcoholism and especially in the treatment of long-standing insulin-dependent diabetes mellitus. Acetiamine Bentiamine Afloqualone has been evaluatedas a successful anti-inflammatory agent with lower back pain patients. A condensed pyrimidin-2-onederivative, proquazone, has been reported to exhibit good NSAID potential [45–51].

Antihypertensive Activity: Many pyrimidine ring containing drugs have exhibited antihypertensiveactivity. A quinozoline derivative, prazosin, is a selective a1-adrenergic antagonist. Its related analoguesbunazosin, trimazosin and terazosin are potent antihypertensive agents. Ketanserin has a similar effectand is an antagonist of both a1-adrenergic and serotonin-S2 receptors. A triaminopyrimidine derivative,minoxidil, whose mechanism of action and therapeutic action are similar to prazosin, has been introducedin therapy for its side effects, in the treatment of alopecia, male baldness etc [51–59].

CNS Activity: Agents involved in this category include sedatives, hypnotic, anticonvulsants, anxiolyticagents, pyrimidine anaesthetics etc. Large variety of barbiturates are used as CNS active agents andare classified as short, intermediate and long acting depending upon duration of action. Risoperidoneis an antipsychotic drug, which is a structural hybrid of butyrophenone and can be used as anxiolytic,antidepressant and antiparkinsonian drug. A pyrimidine analogue, thimylal is a short acting generalanaesthetic drug [60–67].

Pyridazine and Pyridazinone Compounds: In recent years a substantial number of pyridazines andpyridazinones have been reported to possess various biological activities such as antimicrobial, antituber-cular, antifungal, analgesic and anti-inflammatory, phosphodiesterase (PDE) inhibitors, cyclooxygenase(COX) inhibitors, antipyretic, antidiabetic, antifeedant, insecticidal, antihypertensive, antiplatelet, an-ticancer, anticovulsant, anti-HIV, antiasthma & antiallergic, neurological activity, like anti anxiety &depressant, and intermediates for drugs synthesis, agrochemicals and other anticipated biological prop-erties. In particular, a large number of pyridazinone derivatives are well known as therapeutic agents.The review aimed at utilizing pyridazine and Phthalazine derivatives as various biological activities thatprompted us to study these compounds [68–77] Figure 2.

Phthalazine Compounds: The diverse biological activities of various functional derivatives of sub-stituted phtahlazines are well known. Some of the phtahlazines derivatives have found application in

5


Figure 2. Structures of six membered diazine compounds and its biological activities

clinical medicinedue to their pronounced antipyretic, analgesic and cardiovascular activity while othershave shown interesting vasodialator and antihypertensive properties [78, 79]. Phtahlazines bearing asubstitution represent key intermediates in the synthesis of various compounds with highly interestingpharmacological properties. Phtahlazines has been found to be a selective PDE inhibitor or the thrombox-ane synthetase inhibitor and bronchodilator. The phthalazine nucleus has been proved to be a versatilesystem in medicinal chemistry. Moreover, a number of established drug molecules [80] are accessible

6


starting from the corresponding phthalazinones. The development of new and efficient methodologiesfor the synthesis of such potentially bioactive phthalazine derivatives is important [81–83]. Therefore,functionalization of the nucleus continues to be of synthetic interest. In general, most of the structuralmodifications of the parent system have been carried out in order to optimize the biological activity ofdiazines-derived drugs.

Pyridazine and phthalazine drugs: Pyridazine and phthalazine derivatives are found in skeleton ofsome commercially available drugs. For instance, Apresoline contains hydralazine 4 as a pyridazinederivative that is used to treat hypertension for pregnant [84]. Brantur is other drug which is usedfor the treatment of depression and it includes minaprine as an active compound. Azaphen is anothermedicine including pyridazine ring. It has pipofezine structure which is tricyclic anti-depressant havinga sedative effect [85]. Pyridazine derivatives have different functionalities in their structures. Forexample, pyridate has thiocarbonate composition, credazine 8 comprises the ether linkage and pyridafolconsists of alcohol unit. Pyridazinones hold considerable interest relative to the preparation of organicintermediates and physiologically active compounds [86]. They are used as 5-HT2c agonists, which playan important role in emesis, mood, sexuality, sleep and appetite. Moreover, it is proven that pyridazinonesexhibit bronchodilator activity on the cardiovascular system [79] and also inhibited the blood plateletaggregation. Other important pharmacological property of pyridazinone derivatives is antihypertensiveactivity. Pyridazinone derivatives are also found as an inhibitor, such as methylphthalazin-1-one 10which is the inhibitor of acetohydroxy acid synthase (AHAS), an enzyme that speeds up the biosynthesisof branched-chain amino acids including leucine and valine [87]. In the structure of AHAS inhibitor,methylphthalazin-1-one is called phthalazinone. Pyridazinone derivatives like SK&F-93741, its normethylderivative and levosimendan, possess a substituted amino group at para-position of 6-phenyl ring and haveemerged as potent cardiotonic agents with dual inotropic and vasodilatory properties in higher animals[88]. These pyridazinone derivatives have shown good activity against CHF. Besides, arylsubstituted 4,5-dihydro-3(2H)-pyridazinones such as imazodan and Cl 930 reported to show ionotropic properties [89].These pyridazine ring containing drugs have relatively selective inhibitors of cardiac cyclic nucleotidePDE activity.

A series of 6-benzoxazinylpyridazin-3-ones were evaluated for inhibition of cardiac PDE-III andfor positive inotropic activity. 6-(3,4-Dihydro-3-oxo-1,4-(2H)-benzoxazin-7-yl)-2,3,4,5-tetrahydro-5-methyl pyridazin-3-one (bemoradan) was an extremely potent and selective inhibitor of PDE-III and along-acting, potent inotropic vasodilator and management of CHF. Several benzothiazolyl, imidazoben-zothiazolyl, benzothienyl, benzothienopyrimidinyl and quinazolinyl 4,5-dihydro-3(2H)-pyridazinonesexhibited cardiotonic activity, and 6-(4-(benzyl amino)-7-quinazolinyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (KF15232) showed potent cardiotonic activity with Ca2+-sensitizing effect. A series ofanalogues of (E)-4,5-dihydro-6-(2-(4-(1H-imidazol-1-yl) phenyl) ethenyl)-3(2H)-pyridazinone as a vari-ation on the imazodan series were evaluated for hemodynamic activity, cyclic AMP-PDE inhibitoryactivity, and antiplatelet activity. The 4,5-dihydro-6-(2-(4-methoxyphenyl)-1H-benzimidazol-5-yl)methyl-3(2H)-pyridazone exhibited positive inotropic effect. The calcium antagonist pyridazinone-derivativepimobendan is a PDE inhibitor with vasodilating, antihypertension as well as positive inotropic properties.The 6-(4-(2-(3-(5-chloro-2-cyanophenoxy)-2-hydroxypropylamino)-2-methylpropyl amino) phenyl)-4,5-dihydro-5-methyl-3(2H) pyridazinone monoethyl maleate TZC-5665 showed negative chronotropic andinotropic effects, TZC- 5665 showed a non-selective beta-adrenoceptor blocking activity comparableto that of propranolol. In enzyme preparations, TZC-5665 was more potent and selective inhibitorsof PDE-III. Combination of b -adrenoceptor blocking effect of TZC-5665 and positive inotropic effectcould be useful in the treatment of CHF. A potent Ca2+-sensitizer, the effects of the pyridazinone deriva-tive pimobendan, increased force of contraction by sensitizing of the contractile proteins towards Ca2+

7


and by inhibition of PDE-III isoenzymes in a concentration-dependent manner. Levosimendan is apyridazinone-dinitrile derivative belonging to cardiac inotropic drug, Ca2+ sensitizer and a vasodilator.The results indicate a lowering of Ca2+by levosimendan consistent with opening of potassium channelsand a relaxation that is independent of Ca2+. Pimobendan is a benzimidazole-pyridazinone derivative withcalcium-sensitizing properties that increases myocardial contractile force without increasing intracellularcalcium (Ca+2)i. These pimobendan may have a useful adjunctive role in heart failure. Ca2+ sensitizers,a new class of cardiotonic agents, have been shown to exert positive inotropic effects without increasing(Ca+2)i transient. They avoid Ca2+ overload that leads to arrhythmias. Therefore, Ca2+sensitizersmay be useful for the treatment of CHF. MCI-154, 6-(4-(4’-pyridylamino) phenyl)-4,5-dihydro-3(2H)-pyridazinone hydrochloride trihydrate, is a calcium sensitizer that has more potent positive inotropic effectthan that of pimobendan and adibendan [69]. The effect of a cardiotonic agent, MCI-154, showed littleCa2+-sensitizing effect. MCI-154 acts directly on skeletal actomyosin and inhibits a ATPase cycle laterthan the force-generating event. MCI-154, is a Ca2+ sensitizer that has more potent positive inotropiceffect than that of pimobendan 15 and adibendan. Levosimendan 12 increases myocardial contractilityand vasodilator [90].

The pyridazinone derivative, zardaverine is a selective inhibitor of PDE isozymes as a potent bron-chodilator, positive inotropic action and ADP-induced aggregation of human platelets. Zardaverineinhibited the cyclic GMP-inhibitable PDE III from human platelets. The pyridazinone derivative af-fected the calmodulin-stimulated PDE I and the cyclic GMP-stimulated PDE II. Again, this effect wasincreased by activators of adenylate cyclase. These data clearly demonstrate that zardaverine is a selectiveinhibitor of PDE III and PDE IV isozymes [91]. A series of 6-phenyl-3(2H)-pyridazinones with differentsubstituents in the 5-position of the ring were showed platelet-aggregation inhibitors [92]. PC-09, apyridazinone derivative, significantly increased the cyclic AMP level through inhibiting cyclic AMP PDEactivity. The PC-09 is reduced platelet aggregation and intracellular calcium mobilization. The positiveinotropic drug 4,5-dihydro-6-(2-(4-methoxyphenyl)-1H-benzimidazol-5-yl)methyl-3(2H)-pyridazinone(Pimobendan or UD-CG 115 BS) enhances calcium induced contraction from cardiac muscle. Pimobendanis a cardiotonic vasodilator and increases myocardial contractility through calcium sensitization and relax-ation of vascular smooth muscle, probably due to PDE inhibition. Various pyridazines also used in variousdiseases, particularly in cardiac vascular diseases such as amipizone, indolidan, Y-590, motapizone andother. A number of phthalazines drug molecules like Hydralazine, Budralazine, Azelastine, Ponalrestat orZopolrestat etc. The phthalazine derivative azelastine is an antihistamine used in the treatment of allergicrhinitis. Newer agents are more selective inhibitors of the cGMP-inhibited PDE, phthalazine derivativeslike MY5445. Zopolrestat 23 is a phthalazinone derivative that has been inhibits aldose reductase andhas potential use in the prevention of retinopathy, neuropathy, and cataract formation in diabetes. Thechemiluminescence reactions of luminol 24 and related phthalazines, in biological systems where theinherent signal strength and low signal noise ratio contribute to sensitivity. The hydrogen peroxide/luminolsystem has been used for the on-line determination by chemiluminescence of nitric oxide in isolated organperfusates.

Various different phthalazine derivatives also used in various diseases, such as carbazeran 25 andphthalazinol 26. Phthalazine derivatives have been widely applied as therapeutic agents due to theiranticonvulsant, cardiotonic, vasorelaxant, antimicrobial and anti-inflammatory properties [93–96]. Manystudies have been focused on 3(2H)-pyridazinones, which are characterized to possess good analgesicand anti-inflammatory activities and also very low ulcerogenicity [97]. Among the various pyridazinonederivatives, 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (emorfazone) is currently being mar-keted in Japan as an analgesic and anti-inflammatory drug. Moreover, 4-amino-2-methyl-6-phenyl-5-vinyl3(2H)-pyridazinone was seven times more potent than emorfazone as NSAID response. Additionally, 2-

8


substituted 4,5-dihalo-3(2H)-pyridazinone derivatives with high analgesic activity and with no ulcerogenicside effects. The pyridazine derivatives are also widely used in agriculture as plant growth hormone likemaleic hydrazide, herbicides in order to kill pests and unwanted plants such as Norflurazon Pyridazine-Pyridate, Pyrazon or pyramin, NC-170 and NC-184 [85]. Pyridazinones are widely used as pesticides,such as herbicides and insecticides. Some herbicides including pyridazinone ring in their structure havevarious functional groups on the pyridazinone ring. For example, brompyrazon andmetflurazon haveamine group in their skeleton and also they have halides such as bromine and chlorine, respectively.Several pyridazinone herbicides contain carboxylic acid as a functional group, such as flufenpyr andoxapyrazon. Important pyridazinone herbicide is pyridaphenthion. The combination of two or moreheterocyclic and non heterocyclic systems enhances the biological profile many-fold than its parent nuclei.

3. DISCUSSION

The chemistry of nitrogen heteroatom containing heterocyclic organic compounds is becoming morepopular in the area of research. Diazines and related compounds have shown diverse biological activities.They bind to physiological targets or receptors, producing many possible mechanisms of actions. Diazinesare inexpensive and easily synthesized, and therefore have been examined as different biological activities.A slight variation in the substitution pattern on the diazines nucleus often causes a marked difference inactivities and therefore diazines with various substituents are being synthesized and tested for activities insearch of better medicinal agents and great interest has arisen in the design and synthesis of new diazinescompounds to explore their potent activities against various diseases or disorders. The diazines nucleus,which has a useful structure for further molecular exploration for the development of new derivativeswith different biological activities, has received much attention in recent years. Diazines derivatives areof interest because of their pharmacological properties [98–108]. The majority of essential life-scienceproducts contain at least one heterocyclic subunit within their structures and therefore heterocyclicchemistry is essential part of the pharmaceutical industry. A wide variety of receptors have preciousbiological activity due to their rigid structures and functional heterocyclic generally possess drug-likebelongings. In order to further explore chemical space available for pharmaceutical applications, thereis a continued demand for the development of new diazine heterocyclic core scaffolds that have novelstructures and bear functionality and subsequent hit-to-lead medicinal chemistry development. Thesesix membered saturated moiety containing nitrogen atoms can be explore to synthesize many of itsanalogous which can be effectively and successfully exploit to obtained the new molecule which showsbetter biological response as to treat psychological and neurological disorders. Since the prevalence ofmental health problems, particularly psychosis, schizophrenia, depression and anxiety, in the generalpopulation is around one in six people, and around 40% of people with mental health problems will havesymptoms of both anxiety and depression. Drug acting on the CNS include the centrally acting (mainlyopoid) analgesics, anti-epileptics and anti-Parkinson agents, as well as those for psychiatric disorders.Based on the literature it may be conclude that six membered saturated nitrogen containing rings areimportant and it throws attention to set the mind of researchers to carry out the work for developing itsvarious analogous used in neurological & psychological disorders which can ultimately beneficial forhumans beings [109–118]. Data will give the idea to further explore with the six membered saturated ringcontaining other heteroatoms like oxygen, sulphur etc.

9


4. CONCLUSION

Diazines occupy a distinct and unique place in our life. This heterocyclic moiety has great biologicaland medicinal significance. A vast literature has been accumulated over the years and chemistry ofdiazines continues to be a blossoming field. The biological profiles of this new generation of diazinesrepresent much progress with regard to the older compounds. The diazines scaffold, due to its easyfictionalization at various position of ring has found considerable pharmaceutical interest as the corestructure of a wide variety of bio-active compounds. During the past few years, we have investigated thesynthesis and biological activity of various new representatives of this “diazines” ring system, mainlyfocusing on potential biological active agents. The title ring system now became interesting in searchof new and more potent compounds with lesser side effect. Based on the information, the need arose toprepare a focused compound library of diazines bearing various substituents at the ring system. Despitetheir simplicity, surprisingly few representatives of this general structure have been known so far. Thechemists, pharmacologists and researchers have taken attention on diazine compounds due to its diversebiological potential and other anticipated activities. These are used as valuable intermediates and valuableagro-chemicals. This diversity in the pharmacotherapeutical profile has attracted the attention of manyresearchers to explore this nucleus against several other activities also. By the present scenario it can beconcluded that diazines have a great potential which remain to be disclosed till date. The reviewed hasshown a wide spectrum of biological activities. The biological profile of these generations of diazinesrepresents much progress with regards. Diazine nucleus is one of the most important heterocyclesexhibiting remarkable pharmacological activities. The present review provides a broad view of thebiological and medicinal activity possessed by compounds having diazine nucleus.

References

[1] A. Ahmed, K. I. Molvi, S. Nazima, I. Baig, T. Memon, and Rahil Journal of Chemical & Pharma-ceutical Research, vol. 4, no. 1.

[2] A. Martin, J. Delgado, and W. Remers, “Wilson and gisvolds textbook of organic medicinal andpharmaceutical chemistry,” Lipincott-Raven, Philadelphia, p. 208, 1998.

[3] M. D. Remington, “The science and practice of pharmacy,” Pennsylvania: Mack PublishingCompany, 1995.

[4] R. Mishra and I. Tomar Inter J. Pharm Sci. & Res., vol. 2, no. 4, pp. 758–771, 2011.[5] A. H. El-Wahab, H. M. Mohamed, A. M. El-Agrody, M. A. El-Nassag, and A. H. Bedair, “Synthesis

and biological screening of 4-benzyl-2h-phthalazine derivatives,” Pharmaceuticals, vol. 4, no. 8,pp. 1158–1170, 2011.

[6] H. M. Faidallah, K. A. Khan, and M. S. Makki, “Synthesis and biological evaluation of new fusedisoxazolo [4, 5-d] pyridazine derivatives,” Journal of the Chinese Chemical Society, vol. 58, no. 2,pp. 191–198, 2011.

[7] M. Asif, A. Singh, et al., “In-vivo anticonvulsant and in-vitro antimycobacterial activities of 6-arylpyridazine-3(2h)-one derivatives,” American Journal of Pharmacological Sciences, vol. 2, no. 1,pp. 1–6, 2014.

[8] L. H. A. S. A. Asif M, Singh A, 2013.[9] L. Asif M, Singh A, 2013.

[10] L. S. A. H. A. Asif M, Anita S, 2011.[11] L. Asif M, Singh A, 2011.

10


[12] M. Gokce, S. Utku, and E. Kupeli, “Synthesis and analgesic and anti-inflammatory activities 6-substituted-3 (2h)-pyridazinone-2-acetyl-2-(p-substituted/nonsubstituted benzal) hydrazone deriva-tives,” European journal of medicinal chemistry, vol. 44, no. 9, pp. 3760–3764, 2009.

[13] I. Rathish, K. Javed, S. Bano, S. Ahmad, M. Alam, and K. Pillai, “Synthesis and blood glucoselowering effect of novel pyridazinone substituted benzenesulfonylurea derivatives,” Europeanjournal of medicinal chemistry, vol. 44, no. 6, pp. 2673–2678, 2009.

[14] S. Cao, X. Qian, G. Song, B. Chai, and Z. Jiang, “Synthesis and antifeedant activity of newoxadiazolyl 3 (2 h)-pyridazinones,” Journal of agricultural and food chemistry, vol. 51, no. 1,pp. 152–155, 2003.

[15] K. Abouzid, M. Abdel Hakeem, O. Khalil, and Y. Maklad, “Pyridazinone derivatives: Design,synthesis, and in vitro vasorelaxant activity,” Bioorganic & medicinal chemistry, vol. 16, no. 1,pp. 382–389, 2008.

[16] W. Malinka, A. Redzicka, and O. Lozach, “New derivatives of pyrrolo [3, 4-d] pyridazinone andtheir anticancer effects,” Il Farmaco, vol. 59, no. 6, pp. 457–462, 2004.

[17] M. Asif, A. Singh, et al., “Development of structurally diverse antitubercular molecules withpyridazine ring.,” Chronicles of Young Scientists, vol. 4, no. 1, 2013.

[18] M. Asif, A. Singh, and A. A. Siddiqui, “The effect of pyridazine compounds on the cardiovascularsystem,” Medicinal Chemistry Research, vol. 21, no. 11, pp. 3336–3346, 2012.

[19] M. Asif, A. Singh, and L. Ratnakar, “Antimicrobial agents: Brief study of pyridazine derivativesagainst some phathogenic microrganisms.,” Journal of Pharmacy Research, vol. 4, no. 3, 2011.

[20] M. Asif and A. Singh, “Exploring potential, synthetic methods and general chemistry of pyridazineand pyridazinone: A brief introduction.,” International Journal of ChemTech Research, vol. 2, no. 2,2010.

[21] G. Thomas, Fundamentals of medicinal chemistry. John Wiley & Sons, 2004.[22] T. KD, “Drugs used in mental illness, essentials of medical pharmacology,” Jaypee Brothers, vol. 4,

2003.[23] R. Rajurkar, V. Agrawal, S. Thonte, and R. Ingale, “Heterocyclic chemistry of quinoxaline and

potential activities of quinoxaline derivatives. a review,” Pharmacophore, vol. 1, no. 2, pp. 65–76,2010.

[24] R. R. Gupta, M. Kumar, and V. Gupta, Heterocyclic Chemistry. Springer Berlin, 1998.[25] J. Joule, “K. mills heterocyclic chemistry, ed,” 2000.[26] M. Amir, S. Javed, and H. Kumar, “Pyrimidine as antiinflammatory agent: A review.,” Indian

journal of pharmaceutical sciences, vol. 69, no. 3, 2007.[27] S. S. Jain MK, 2008.[28] B. Padamshari and V. Vaidya, “Vijayaya kumar ml,” Indian Journal of Heterocyclic. Chem, vol. 12,

pp. 89–94, 2002.[29] T. Naik and K. Chikhalia, “Studies on synthesis of pyrimidine derivatives and their pharmacological

evaluation,” Journal of Chemistry, vol. 4, no. 1, pp. 60–66, 2007.[30] A. Aly, “Synthesis and pharmacological activity of annelated pyrimidine derivatives,” Chinese

Journal of Chemistry, vol. 23, no. 2, pp. 211–217, 2005.[31] D. Singh, A. Mishra, and R. Mishra, “Synthesis and characterization of some antifungal pyrim-

idinone derivatives,” INDIAN JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 14, no. 1,pp. 43–46, 2004.

[32] K. Mogilaiah and G. R. Sudhakar, “Synthesis of pyrazoline, pyrimidine and 1, 5-benzodiazepinederivatives of 1, 8-naphthyridine and evaluation of antibacterial activity,” INDIAN JOURNAL OFCHEMISTRY SECTION B, vol. 42, no. 3, pp. 636–640, 2003.

[33] V. Alagarsamy, U. Pathak, V. Rajasolomon, S. Meena, K. Ramseshu, and R. Rajesh, “Anticancer,11


antibacterial and antifungal activities of some 2-substituted (1, 3, 4) thiadiazolo (2, 3-b) tetrahy-drobenzo (b) thieno (3, 2-e) pyrimidines,” Indian Journal of Heterocyclic Chemistry, vol. 13, no. 4,pp. 347–350, 2004.

[34] R. Vyas, “Udaibhan gahlot s. and verma bl,” Indian J. Heterocyclic Chem, vol. 13, p. 15, 2003.[35] P. Callery and P. Gannett, “Cancer and cancer chemotherapy,” Foyes Principles of medicinal

Chemistry, pp. 934–935, 2002.[36] O. N. Al Safarjalani, X.-J. Zhou, R. H. Rais, J. Shi, R. F. Schinazi, F. N. Naguib, and M. H. el Kouni,

“5-(phenylthio) acyclouridine: a powerful enhancer of oral uridine bioavailability: relevance tochemotherapy with 5-fluorouracil and other uridine rescue regimens,” Cancer chemotherapy andpharmacology, vol. 55, no. 6, pp. 541–551, 2005.

[37] K. J. Singh P and P. K, 2008.[38] S. Pedeboscq, D. Gravier, F. Casadebaig, G. Hou, A. Gissot, F. De Giorgi, F. Ichas, J. Cambar,

and J.-P. Pometan, “Synthesis and study of antiproliferative activity of novel thienopyrimidines onglioblastoma cells,” European journal of medicinal chemistry, vol. 45, no. 6, pp. 2473–2479, 2010.

[39] O. Fathalla, I. Zeid, M. Haiba, A. Soliman, S. I. Abd-Elmoez, and W. El-Serwy, “Synthesis,antibacterial and anticancer evaluation of some pyrimidine derivatives,” World J Chem, vol. 4, no. 2,pp. 127–132, 2009.

[40] A. K. a. I. Talal A, 1996.[41] Raic-Malic, Silvana, M. Grdisa, K. Pavelic, and M. Mintas, “Synthesis and biological evaluation

of the novel purine and pyrimidine nucleoside analogues containing 2, 3-epoxypropyl, 3-amino-2-hydroxypropyl or 2, 3-epoxypropyl ether moieties,” European journal of medicinal chemistry,vol. 34, no. 5, pp. 405–413, 1999.

[42] J. Delgado and W. Remers, “Antineoplastic agents: In wilson and gisvolds textbook of organicmedicinal and pharmaceutical chemistry,” Wilson and Gisvold’s Textbook of Organic Medicinaland Pharmaceutical Chemistry.

[43] N.-O. W. G. of the German Cancer Society et al., “Neuro-oncology working group 01 trial ofnimustine plus teniposide versus nimustine plus cytarabine chemotherapy in addition to involved-field radiotherapy in the first-line treatment of malignant glioma,” Journal of Clinical Oncology,vol. 21, no. 17, pp. 3276–3284, 2003.

[44] B. Kennedy, J. L. Torkelson, and E. Torlakovic, “Uracil mustard revisited,” Cancer, vol. 85, no. 10,pp. 2265–2272, 1999.

[45] M. Belema, A. Bunker, V. Nguyen, F. Beaulieu, C. Ouellet, A. Marinier, S. Roy, X. Yung, Y. Zhang,Martel, and C. Zuci, 2003.

[46] B. Padmashali, V. Vaidya, and M. V. Kumar, “Synthesis and pharmacological evaluation of somenaphtho [2, 1-b] furo [3, 2-d] pyrimidines,” Indian journal of heterocyclic chemistry, vol. 12, no. 2,pp. 89–94, 2002.

[47] A. Cannito, M. Perrissin, C. Luu-Duc, F. Huguet, C. Gaultier, and G. Narcisse, “Synthese etproprietes pharmacologiques de quelques thieno [2, 3-d] pyrimidin-4-one 2-thiones,” EuropeanJournal of Medicinal Chemistry, vol. 25, no. 8, pp. 635–639, 1990.

[48] F. Russo, G. Romeo, N. Santagati, A. Caruso, V. Cutuli, and D. Amore, “Synthesis of newthienopyrimidobenzothiazoles and thienopyrimidobenzoxazoles with analgesic and antiinflamma-tory properties,” European journal of medicinal chemistry, vol. 29, no. 7, pp. 569–578, 1994.

[49] L. HW and K. BY, 2005.[50] L. V. Desenko SM and G. NI, 1995.[51] A. P. S. Ishwaarsinh Rathod S and V. S. S, 2000.[52] K. V. Raj, B. Narayana, B. Ashalatha, and N. S. Kumari, “New thiazoles containing pyrazolopyrim-

idine moiety as possible analgesic agents. i,” Pharmacol. ToXicol, vol. 1, pp. 559–565, 2006.12


[53] A. P. S. Ishwaarsinh Rathod S and V. S. S, 2000.[54] N. SK and S. Ambekar, 1998.[55] H. Hara, M. Ichikawa, H. Oku, M. Shimazawa, and M. Araie, “Bunazosin, a selective a1-

adrenoceptor antagonist, as an anti-glaucoma drug: Effects on ocular circulation and retinalneuronal damage,” Cardiovascular drug reviews, vol. 23, no. 1, pp. 43–56, 2005.

[56] P. Scott, P. Meredith, A. Kelman, D. Hughes, and J. Reid, “The effects of age on the pharmacokinet-ics and pharmacodynamics of cardiovascular drugs: application of concentration-effect modeling.2. acebutolol,” American journal of therapeutics, vol. 2, no. 8, pp. 537–540, 1995.

[57] W. Ganzevoort, A. Rep, G. J. Bonsel, J. I. de Vries, and H. Wolf, “Plasma volume and blood pressureregulation in hypertensive pregnancy,” Journal of hypertension, vol. 22, no. 7, pp. 1235–1242,2004.

[58] A. Gupta, H. Kayath, S. Ajit, S. Geeta, K. Mishra, et al., “Anticonvulsant activity of pyrimidinethiols,” Indian Journal of Pharmacology, vol. 26, no. 3, p. 227, 1994.

[59] W. WM, “Ann. pharmacotherapy,” 1994.[60] S. Q. Wang, L. Fang, X. Liu, and K. Zhao, “Design, synthesis, and hypnotic activity of pyrazolo [1,

5-a] pyrimidine derivatives,” Chinese Chemical Letters, vol. 15, no. 8, pp. 885–888, 2004.[61] H. R. Howard and T. F. Seeger, “. novel antipsychotics,” Annual Reports in Medicinal Chemistry,

vol. 28, pp. 39–47, 1993.[62] S. Rehaman and Y. Rajendra Prasad, “Phani kumar, bharath kumar,” Synthesis and anti-histaminic

activity of some novel pyrimidines. Saudi Pharm. Journal, vol. 17, pp. 255–258, 2009.[63] A. E. Rashad, A. H. Shamroukh, R. E. Abdel-Megeid, A. Mostafa, R. El-Shesheny, A. Kandeil,

M. A. Ali, and K. Banert, “Synthesis and screening of some novel fused thiophene and thienopy-rimidine derivatives for anti-avian influenza virus (h5n1) activity,” European journal of medicinalchemistry, vol. 45, no. 11, pp. 5251–5257, 2010.

[64] A. Agarwal, K. Srivastava, S. Puri, S. Sinha, and P. Chauhan, “A small library of trisubstitutedpyrimidines as antimalarial and antitubercular agents,” Bioorganic & medicinal chemistry letters,vol. 15, no. 23, pp. 5218–5221, 2005.

[65] E. A. Meade, M. Sznaidman, G. T. Pollard, L. M. Beauchamp, and J. L. Howard, “Anxiolyticactivity of analogues of 4-benzylamino-2-methyl-7h-pyrrolo [2, 3-d] pyrimidines,” Europeanjournal of medicinal chemistry, vol. 33, no. 5, pp. 363–374, 1998.

[66] J. Chamanlal Shishoo, S. Kishore Jain, S. Ishwarsinh Rathod, J. Bipin Thakkar, B. Samir Brahmb-hatt, R. B. Thakorbhai, and R. G. K.

[67] K. Jain, T. Chitre, P. Miniyar, M. Kathiravan, V. Bendre, V. Veer, S. Shahane, and C. Shishoo,“Biological and medicinal significance of pyrimidines,” CURRENT SCIENCE-BANGALORE-,vol. 90, no. 6, p. 793, 2006.

[68] A. A. Siddiqui, R. Mishra, and M. Shaharyar, “Synthesis, characterization and antihypertensiveactivity of pyridazinone derivatives,” European journal of medicinal chemistry, vol. 45, no. 6,pp. 2283–2290, 2010.

[69] H. Chen, X. Cui, H. Zhao, L. Zhao, J. Lu, and B. Wu, “Inotropic effects of mci-154 on rat cardiacmyocytes.,” Sheng li xue bao:[Acta physiologica Sinica], vol. 56, no. 3, pp. 301–305, 2004.

[70] H. Xu, X.-M. Zou, Y.-Q. Zhu, B. Liu, H.-L. Tao, X.-H. Hu, H.-B. Song, F.-Z. Hu, Y. Wang, andH.-Z. Yang, “Synthesis and herbicidal activity of novel a , a , a-trifluoro-m-tolyl pyridazinonederivatives,” Pest management science, vol. 62, no. 6, pp. 522–530, 2006.

[71] F. M. Abdelrazek, F. A. Michael, and A. E. Mohamed, “Synthesis and molluscicidal activity ofsome 1, 3, 4-triaryl-5-chloropyrazole, pyrano [2, 3-c] pyrazole, pyrazolylphthalazine and pyrano [2,3-d] thiazole derivatives,” Archiv der Pharmazie, vol. 339, no. 6, pp. 305–312, 2006.

[72] C. Allerton, M. D. Andrews, J. Blagg, D. Ellis, E. Evrard, M. P. Green, K. Liu, G. McMurray,13


M. Ralph, V. Sanderson, R. Ward, and L. Watson Bioorg. Med. Chem. Lett., vol. 1, no. 19, pp. 5791–5795, 2009.

[73] Q. Huang, Y. Kong, M. Liu, J. Feng, and Y. Liu, “Effect of oxadiazolyl 3 (2h)-pyridazinone on thelarval growth and digestive physiology of the armyworm, pseudaletia separata,” Journal of insectscience, vol. 8, 2008.

[74] R. W. L. Derson, V.; Ward, 2009.[75] T. Wang, Y. Dong, L.-C. Wang, B.-R. Xiang, Z. Chen, and L.-B. Qu, “Design, synthesis and

structure-activity relationship studies of 6-phenyl-4, 5-dihydro-3 (2h)-pyridazinone derivatives ascardiotonic agents,” Arzneimittelforschung, vol. 58, no. 11, pp. 569–573, 2008.

[76] A. S. Youssef, M. Marzouk, H. M. Madkour, A. M. El-Soll, and M. El-Hashash, “Synthesis of someheterocyclic systems of anticipated biological activities via 6-aryl-4-pyrazol-1-yl-pyridazin-3-one,”Canadian journal of chemistry, vol. 83, no. 3, pp. 251–259, 2005.

[77] T. Maemoto, M. Tada, T. Mihara, N. Ueyama, H. Matsuoka, K. Harada, T. Yamaji, K. Shirakawa,S. Kuroda, A. Akahane, et al., “Pharmacological characterization of fr194921, a new potent, selec-tive, and orally active antagonist for central adenosine a1 receptors.,” Journal of pharmacologicalsciences, vol. 96, no. 1, pp. 42–52, 2004.

[78] S. Demirayak, A. C. Karaburun, and R. Beis, “Some pyrrole substituted aryl pyridazinone andphthalazinone derivatives and their antihypertensive activities,” European journal of medicinalchemistry, vol. 39, no. 12, pp. 1089–1095, 2004.

[79] M. Yamaguchi, K. Kamei, T. Koga, M. Akima, T. Kuroki, and N. Ohi, “Novel antiasthmaticagents with dual activities of thromboxane a2 synthetase inhibition and bronchodilation. 1. 2-[2-(1-imidazolyl) alkyl]-1 (2h)-phthalazinones,” Journal of medicinal chemistry, vol. 36, no. 25,pp. 4052–4060, 1993.

[80] M. Napoletano, G. Norcini, F. Pellacini, F. Marchini, G. Morazzoni, P. Ferlenga, and L. Pradella,“Phthalazine pde4 inhibitors. part 2: the synthesis and biological evaluation of 6-methoxy-1, 4-disubstituted derivatives,” Bioorganic & medicinal chemistry letters, vol. 11, no. 1, pp. 33–37,2001.

[81] M. M. Abdel-Khalik, S. M. Agamy, and M. H. Elnagdi, “Chemistry of 2-arylhydrazonopropanals:novel synthesis of 1, 6-dihydropyridazines and 5-heteroaryl substituted pyrazolo [1, 5-a] pyrim-idines and pyrazolo [3, 4-b] pyridines,” Synthesis, vol. 2001, no. 12, pp. 1861–1865, 2001.

[82] T. Haack, R. Fattori, M. Napoletano, F. Pellacini, G. Fronza, G. Raffaini, and F. Ganazzoli, “Phtha-lazine pde iv inhibitors: Conformational study of some 6-methoxy-1, 4-disubstituted derivatives,”Bioorganic & medicinal chemistry, vol. 13, no. 14, pp. 4425–4433, 2005.

[83] J. Epsztajn, Z. Malinowski, J. Z. Brzezinki, and M. Karzatka, “Application of organolithium andrelated reagents in synthesis; part 26. synthetic strategies based on directed ortho-metalation:Synthesis of 4-methyl-2h-phthalazin-1-ones,” Synthesis, vol. 2001, no. 14, pp. 2085–2090, 2001.

[84] P. Vigil-De Gracia, M. Lasso, E. Ruiz, J. C. Vega-Malek, F. T. de Mena, and J. C. Lopez, “Severehypertension in pregnancy: Hydralazine or labetalol: A randomized clinical trial,” EuropeanJournal of Obstetrics & Gynecology and Reproductive Biology, vol. 128, no. 1, pp. 157–162, 2006.

[85] R. L. Kellogg, R. Nehring, A. Grube, D. W. Goss, and S. Plotkin, “Environmental indicators ofpesticide leaching and runoff from farm fields.,” 2000.

[86] S. A. Hovakimyan, A. V. Babakhanyan, V. S. Voskanyan, V. E. Karapetian, G. A. Panosyan, andS. T. Kocharian, 2004.

[87] Y.-X. Li, Y.-P. Luo, Z. Xi, C. Niu, Y.-Z. He, and G.-F. Yang, “Design and syntheses of novelphthalazin-1 (2 h)-one derivatives as acetohydroxyacid synthase inhibitors,” Journal of agriculturaland food chemistry, vol. 54, no. 24, pp. 9135–9139, 2006.

[88] D. Kumar, R. Carron, C. La Calle, D. Jindal, and R. Bansal, “Synthesis and evaluation of 2-14


substituted-6-phenyl-4, 5-dihydropyridazin-3 (2h)-ones as potent inodilators,” Acta pharmaceutica,vol. 58, no. 4, pp. 393–405, 2008.

[89] S. Archan and W. Toller, “Levosimendan: current status and future prospects,” Current Opinion inAnesthesiology, vol. 21, no. 1, pp. 78–84, 2008.

[90] T. Wang, Y. Dong, L. Wang, and Chen, 2007.[91] E. Sotelo, A. Coelho, and E. Ravina, “Pyridazine derivatives 32: stille-based approaches in the

synthesis of 5-substituted-6-phenyl-3 (2h)-pyridazinones,” CHEMICAL AND PHARMACEUTICALBULLETIN-TOKYO-, vol. 51, no. 4, pp. 427–430, 2003.

[92] E. Sotelo, A. Coelho, and E. Ravina, “Pyridazine derivatives 32: stille-based approaches in thesynthesis of 5-substituted-6-phenyl-3 (2h)-pyridazinones,” CHEMICAL AND PHARMACEUTICALBULLETIN-TOKYO-, vol. 51, no. 4, pp. 427–430, 2003.

[93] P. G. Tsoungas and M. Searcey, “A convenient access to benzo-substituted phthalazines as potentialprecursors to dna intercalators,” Tetrahedron Letters, vol. 42, no. 37, pp. 6589–6592, 2001.

[94] R. Sivakumar, S. Kishore Gnanasam, S. Ramachandran, and J. Thomas Leonard, “Pharmacologicalevaluation of some new 1-substituted-4-hydroxy-phthalazines,” European journal of medicinalchemistry, vol. 37, no. 10, pp. 793–801, 2002.

[95] S. Demirayak, A. C. Karaburun, I. Kayagil, K. Erol, and B. Sirmagul, “Some pyridazinone andphthalazinone derivatives and their vasodilator activities,” Archives of pharmacal research, vol. 27,no. 1, pp. 13–18, 2004.

[96] D. S. Dogruer, E. Kupeli, E. Yesilada, and M. F. Sahin, “Synthesis of new 2-[1 (2h)-phthalazinon-2-yl] acetamide and 3-[1 (2h)-phthalazinon-2-yl] propanamide derivatives as antinociceptive andanti-inflammatory agents,” Archiv der Pharmazie, vol. 337, no. 6, pp. 303–310, 2004.

[97] T. Onkol, D. Dogruer, S. Ito, and M. Sahin, “Synthesis and antinociceptive activity of (5-chloro-2-benzothiazolinon-3-yl) acetamide derivatives,” Archiv der Pharmazie, vol. 333, no. 10, pp. 337–340,2000.

[98] T. Costas, P. Besada, A. Piras, L. Acevedo, M. Yanez, F. Orallo, R. Laguna, and C. Teran, “Newpyridazinone derivatives with vasorelaxant and platelet antiaggregatory activities,” Bioorganic &medicinal chemistry letters, vol. 20, no. 22, pp. 6624–6627, 2010.

[99] A. M., 2012.[100] G. Aleeva, G. Molodavkin, and T. Voronina, “Comparison of antidepressant effects of azafan,

tianeptine, and paroxetine,” Bulletin of experimental biology and medicine, vol. 148, no. 1, pp. 54–56, 2009.

[101] A. A. K. T., 2011.[102] B. I., 2009.[103] B. I., “Possible role of d-serine in the pathophysiology of alzheimer disease,” Progress in Neuro-

Psycho-pharmacology & Biological Psychiatry, vol. 28, pp. 173–180, 2004.[104] J. Block and J. Beale Jr, “Wilson and gisvolds textbook of organic medicinal and pharmaceutical

chemistry,” 2004.[105] M. Cenicola, D. Donnoli, L. Stella, C. De Paola, M. Costantino, E. Abignente, F. Arena, E. Luraschi,

and C. Saturnino, “Research on heterocyclic compounds. antiinflammatory activity of some imidazo(1, 2-c) pyrimidine derivatives,” Pharmacological research, vol. 22, pp. 80–81, 1990.

[106] N. Kakui, F. Yokoyama, M. Yamauchi, K. Kitamura, T. Imanishi, T. Inoue, and T. Koyama,“Anxiolytic-like profile of mirtazapine in rat conditioned fear stress model: Functional significanceof 5-hydroxytryptamine 1a receptor and a1-adrenergic receptor,” Pharmacology Biochemistry andBehavior, vol. 92, no. 3, pp. 393–398, 2009.

[107] E. John, “Annual reports in medicinal chemistry,” 2009.[108] M. N., 2009.

15


[109] P. A. Matos LD, 2006.[110] A. B. Padavala, V. V. Prasanth, S. A. Jayanthi, A. Vadlamani, and S. Chitti, “Journal of chemical

and pharmaceutical research,” J. Chem, vol. 2, no. 2, pp. 147–162, 2010.[111] C.-U. Pae, “Low-dose mirtazapine may be successful treatment option for severe nausea and

vomiting,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 30, no. 6,pp. 1143–1145, 2006.

[112] N. Pai, D. Dubhashi, S. Vishwasrao, and D. Pusalkar, “An efficient synthesis of neuroleptic drugsunder microwave irradiation,” Journal of Chemical and Pharmaceutical Research, vol. 2, no. 5,pp. 506–517, 2010.

[113] G. L. Patrick, An introduction to medicinal chemistry. Oxford university press, 2013.[114] G. K. Rao, R. Kaur, and P. S. Pai, “Synthesis and biological evaluation of some dibenzazepine

analogs,” Journal of Chemical and Pharmaceutical Research, vol. 2, no. 1, pp. 489–496, 2010.[115] S. NA., 2009.[116] S. C. Singh MO, Bhaduaria RS.[117] M. J. Smith MB, “Advanced organic chemistry: Reactions, mechanisms, and structure wiley-

interscience,” 2001.[118] “Wilson & gisvolds textbook of organic medicinal & pharmaceutical chemistry, 11th edition..”

16

About This Journal STOC is an open access journal published by Scientific Online Publishing. This journal focus on the following scopes (but not limited to): ¾ Bioorganic Chemistry ¾ Chemical Biology ¾ Medical Chemistry ¾ Natural Products Chemistry ¾ Organic Reactions

¾ Organic Synthesis ¾ Organometallic & Microwave Chemistry ¾ Physical Organic Chemistry ¾ Supramolecular Chemistry ¾ Synthesis of Functional Materials ¾

Welcome to submit your original manuscripts to us. For more information, please visit our website: http://www.scipublish.com/journals/STOC/ You can click the bellows to follow us: � Facebook: https://www.facebook.com/scipublish � Twitter: https://twitter.com/scionlinepub � LinkedIn: https://www.linkedin.com/company/scientific-online-publishing-usa � Google+: https://google.com/+ScipublishSOP

SOP welcomes authors to contribute their research outcomes under the following rules: ¾ Although glad to publish all original and new research achievements, SOP can’t bear any

misbehavior: plagiarism, forgery or manipulation of experimental data.

¾ As an international publisher, SOP highly values different cultures and adopts cautious attitude towards religion, politics, race, war and ethics.

¾ SOP helps to propagate scientific results but shares no responsibility of any legal risks or harmful effects caused by article along with the authors.

¾ SOP maintains the strictest peer review, but holds a neutral attitude for all the published articles. ¾ SOP is an open platform, waiting for senior experts serving on the editorial boards to advance the

progress of research together.

http://www.scipublish.com/journals/STOC/

https://www.facebook.com/scipublish

https://twitter.com/scionlinepub

https://www.linkedin.com/company/scientific-online-publishing-usa

https://google.com/+ScipublishSOP

Documents

The Pharmacological Importance of Some Diazine Containing ... · Diazines focus our attention because of their easy ﬁctionalization, which makes them attractive synthetic compounds