Studies on Bioactive Tetrahydro Pyrimidine

Studies on Bioactive Tetrahydro PyrimidineChapter- 1 oecumenic gate 1Chapter 1General world1.1 Heterocycles in drug huskingCurrently pharmaceutical manufacturing is face up rough(prenominal) problems for research and readyment due to high costs and uniform existence of moieties in these geezerhood.According to research of man genome we got assumption that at least 1000 genes subatomic particleic number 18 involved in set and non identified complaint. For that research about 20,000 human genome had been decoded.Genetic science suggests that we put one over to develop 5,000-10,000 untried drugs1.be driving these genes atomic number 18 linked with five and ten protein molecule. So we use up to focus in development of low molecular weight drugs. The compounds mustiness be containing specific pharmacokinetic and toxicological properties, which keister show the properties of drugs.In these twenty-four hour periods scientists surrender many techniques to speed up the drug disco very process, standardised combinatorial chemistry, microwave-assisted organic synthesis, and high- throughput purification2. Actually, it is very difficult to select moiety with slight molecular weight because less than 500 atomic mass unit of measurement is 10200, of which only 1060 may possess drug-like propertiesThe proportion is one part in 1057, or roughly the ratio of the mass of one proton to the mass of the solarise The issue is therefore the selection of new molecules from this con emplacementrable universe that have the potential to be biologically active3.It is important to do research exit on medicinal chemistry to synthesis the biologically active cyclic aromatic heterocycles which should be easily available commercially too.Here is the proclivity of available bicyclic heterocycles is mainly limited to well- kip downn nitrogen containing compounds, such as quinazolines (1), indoles Chapter- 1 General world 2(2) and benzimidazoles (3).Esatlished e xemplars of inside substructures acknowledge benzodiazepines (4), coumarins (5), quinoxalines (6), benzofurans (7) and benzothiophenes (8)5. In order to improve the hit rate in HTS campaigns,.This library is very useful to develop active compound in many anatomy of biological assays.So many scientists have utilized these structures in such a manner. For example, Nicolau K. C. et al. constructed a library based on the benzopyran (9) privileged scaffold6,whereas Schultz P. G. et al. made use of the purine (10) scaffold7. Chapter- 1 General insertion 3O (9) Benzopyran N N NH N (10) Purine The benzopyran and purine privileged scaffold1.2 Nomenclature of the amalgamated ring systemAs the future(a) chapters deal with the synthesis of bicyclic f utilise ring systems, its nomenclature is herewith shortly reviewed. The nomenclature follows the pastime rules(1) The individual atoms atomic number 18 recognized without any application of fuse ring system.(2) The arouse component is represented in the fusion name by citing it closing in the name. The kindle component is the one with highest priority according to the following criteria(a) heterocyclic compounds contains elements in ring.(b) a component containing the larger ring.(c) there be so many atoms of elements in the ring.(d) a component containing the greater variety of heteroatoms.(3) The attached component is then added as a prefix to the pargonnt component. In the name of the prefix, the terminal e is changed to o.(4) The bonds of the p atomic number 18nt component are indicated by a, b, cstarting with the bond normally occupying the 1,2 positions. The atoms of the attached component are numbered as usual, following the order of numbers in the passe-partout heterocycle.(5) The numbering of the final condensed heterocycle is carried out independently, starting at an atom adjacent to a bridged-head atom, whereby heteroatoms receive the smallest possible number. Chapter- 1 General knowledgeability 4 1.3 Objective-Synthesis and biological evaluation of 1,2,3,4 tetra hydro pyrimidines leave behind be done.To study the pharmacological and medicinal applicationapplication of synthesized compound. Viz. antimicrobial, immunodilator, antituberculosis, antielergic and radioprotectves.The synthesis of (AB 101 to 145) will be achieved by acid catalysed cyclocondensation of N-(substituted)-3-oxobutanamide, substituted urea differential coefficients and 4-(phenoxymethyl) benzaldehyde.The products will be eliminated by spectras,. The impertinently synthesized compounds will be subjected to various biological activities viz., antimicrobial, antineoplastic etc..The synthesis of (AB 146 to 190) will be achieved by acid catalysed cyclocondensation of N-(substitutedphenyl)-4-methyl-3-oxopentanamide, substituted urea and 4-(phenoxymethyl) benzaldehyde.The products will be break up by spectras.The newly synthesized compounds will be subjected to various biological activities viz., antimicrob ial, anticancer etc.Chapter- 1 General Introduction 51.4 Some biologic importance of pyrimidines and related heterocyclesRecently genetical science is a vast subject of research. To study genetical science, DNA must be decoded. and we know that In the constituents of nucleic acids likewise pyrimidine exists in form of base. This theory helps give-and-take of AIDS. The discovery of pyrimidine is itself a big revolution in medical science.Some examples of pyrimidine derivatives are given below which are existing in nucleic acid.(1) reveals diabetogenic action in a number of animals8.. Chapter- 1 General Introduction 61.5 medicinal significance of pyrimidines and related heterocycles.During the last 20 years, the drugs containing pyrimidine are very useable as chemotherapeutic agents .1.5.1 Antineoplastics and anticancer agentsSome other examples of pyrimidine antimetabolite are mopidamol (15)18, nimustine (16)19, raltitrexed (17)20, uramustine (18)21 and trimetrixate (19)22. 1--D- Arabinosylcytosine (Ara-C, 20)23 . These compounds are serviceable in intervention of cancer and herpes virus infection.While Gemcitabine (21), is recyclable in the treatment of murine solid tumours24. Chapter- 1 General Introduction 81.5.2 Drugs for hyperthyroidismHere are the examples of drug for hyperthyroidism without side effects25.2-Thiouracil (9c), , Propylthiouracil (9d) thiobarbital (9e)1.5.3 Antifolates, antibacterials and antiprotozoals Chapter- 1 General Introduction 9 Chapter- 1 General Introduction 101.5.4 Sulfa drug 1.5.5 Antivirals and anti-AIDS Pyrimidine is containing antiviral properties also. The most democratic derivative is 5-Iododeoxyuridine(IDU) (31)37. Chapter- 1 General Introduction 11 Chapter- 1 General Introduction 12 Chapter- 1 General Introduction 131.5.6 Antibiotics Pyrimidine are of multi usable important in medical significance they are nice antibiotics also. (42), is used to prevent staphylococcal infections45. While (43), is a cytosine derivat ive and it is useful in treatment of mycobacteria Gram-positive and Gram-negative bacteria46. The other (44) and (45)45. And some wide spectrums are Puromycin (46) phleomycin (47a), bleomycin (47b) are containing the pyrimidine ring. tubercidine (48) is also antibiotic which is used as antitumour 46. Bleomycin is an effective derivative for tumor like Hodgkins lymphoma and disseminated testicular cancer47. Chapter- 1 General Introduction 141.5.7 Antifungals Very common disease found on skin, is fungal infection. But Pyrimidine derivatives are very helpful to solve this problem also because they exhibit antifungal properties also. Flucytosine (49)48 is containing fluorine. And widely strains of candida and Cryptococcus49. And for the treatment of aphthous ulceration Hexitidine50 (50) is used. Chapter- 1 General Introduction 151.5.8 Anthelmentics Sometime the diligent body creates animal with a long thin body having no legs and no bones are called worms. they are of two types pinworm s and roundworms51 .They may cause parasitic attack to body. Pyrantel pamoate (51) is a pyrimidine derivative which can depolarize . 1.5.9 Antitubercular drugs previously only PABA was known antitubercular drug, now a days pyrimidine derivatives also popular in market like Capreomycin (52).which is made by Streptomyces genus Capreolus and used as second-linebacteriostatic antituberculin drug 52, 53. Chapter- 1 General Introduction 16In comparison of p-aminosalicyclic acid , Viomycin (53) is more tuberculostatic generally It isused in the treatment of experimental T.B. 1.5.10 CNS active agents 1.5.10.1 Sedative/Hypnotic/ anticonvulsant drug agents Anxiolytic, sedative and hypnotic compounds are of very interest and important in medical science. They may have short time or longtime(prenominal) effect to act on body.54, 55 Barbiturates compound series have the needed properties to act as Anxiolytic, sedative and hypnotic compounds. and secobarbital are popular as hypnotic barbiturates 56 among medical science users. Hexobarbital, cyclobarbital and propallylonal are popular sedative, hypnotics57. In 1932 Eli Lilly58 was the first researcher of secbutabarbital which was introduce in market with the name of barbitone (8) in starting of twentieth century. Chapter- 1 General Introduction 171.5.10.2 Anxiolytic agents The depression and anxiousness of body, twain action are require in the surgery science. And these two actions are psychotic disease also. Generally psychoanalysts are blessed of these pyrimidine compounds having the psychoactive properties to treat psychosis. buspirone (55), is used to settle anxiety disorders.. It acts as sedative, anticonvulsant and muscle- relaxant effects59. anxiolytic action at law is a good example of our interest62. mezilamine (57) is well known as an antipsychotic agent63. Risoperidone (58) is used as antipsychotic. Effective for anti parkinsonian drug64 1.5.10.3 Pyrimidine anaesthetics Anaesthetics actions are require in the s urgery science. Thimylal (59) is used for minor surgery. This compound is family member of pyrimidine.65,66. Saxitoxin (60)65 dinoflagellates so, it is pyrimidine containing natural source.1.5.10.4 Diuretics and uricosuri make off fluids, with the result that we need to urinate more often th. xanthine derivatives (61) are members of amalgamate pyrimidine family. caffeine (61a)67, etamiphylline (61b)68, lomiphylline (61c)69, etophylline70 (61d), theophylline (61e)67 and theodrendaline (61f)71 are commanding examples of this problem. 1.5.11.1 Antihypertensivespyrimidine derivatives are effective as antihypertensive also. Examples are Prazosin (64a), is member of quinozoline family, and it is 1-adrenergic antagonist74, 75. Other are bunazosin (64b)76, terazosin (64c)77 and trimazosin Chapter- 1 General Introduction 19(64d)78, ketanserin (65)79 and serotonin-S2 is receptor. It is a triaminopyrimidine derivative, minoxidil (66), can be considered similar to Prazosin,by means of action. These drugs are hopeful in treatment of alopecia, male baldness80. More examples of antihypertensives81, 82. Alfuzocin (67)81, is as effective as urapidil (68)82 ,prescribes for urinary barricade of prostate hyperplasia. 1.5.11.2 Vasodilators This drugs are highly require and demanding in the fast feeling the cases of cardiovascular disorder are increasing day by day .in activity of daily life forbearing is attacked by Parkinsons syndrome in some cases. For this disease xanthine derivatives are used in broad level. cardiovascular disorders83. xantinol nicotinate84 (70b), containing value of nicotinic acid is helpful to support vascular disorders and pimephylline (70a) and pyridophylline85 (70c). A new dopamine stimulant, pirebidil (71)86 is used in ADL( Activity of DailyLiving) for the patient of Parkinsons syndrome. Chapter- 1 General Introduction 201.5.11.3 Cardiotonics/Bronchodialators Bronchitis is an illness like a very bad cough,in which our bronchial tubes become sore and infected. Important pyrimidine derivatives acting as drugs are xanthine derivatives theophylline (61e), aminophylline (72a)87 andproxyphylline (72b)87. Chapter- 1 General Introduction 211.5.12 Antihistaminic pyrimidines Histamine affects at present to central nervous system. This is very sensitive to our body and needed to bring round very sharply. Low or higher dose of the medicine may cause dangerous effect to body.Taziphylline (73) is more effective than astemizole and terfenadine88. Other example is temelastine (73a)89. With reference of Radiolabelled studies it came to know that it does not penetrate the Central nervous system. piece Icotidine (73b), lacks Central nervous system (CNS) activity. It is working effectively on both H1 and H2 receptors90. Pemirolast (74)91, is used for severe asthma and proved best pyrimidine derivative. piprinhydrinate (75)92 is also good medicine having pyrimidine. 1.5.13 Analgesics and NSAID drugsMost common problems are seemed in human cr eation are alcoholism and diabetes mellitus .for these different problems many pyrimidine derivatives are being used like Acetiamine (76a)93, bentiamine (76b)93 and Chapter- 1 General Introduction 22fursultiamine (76c)94 which are lipid-soluble forms of thiamine (vitamin B1) For lower back pain patients Afloqualone (77)95 is the best anti-inflammatory medicine. Epirazole (78)96 and Proquazone (81)99are proved better medicine because of Nonsteroidal character (anti-inflammatory drugs), Ademetionine (79)97 is basic drug of glucosamine and chondroitin therapy. Octotiamine (80)98, is derivative of vitamin B1. Chapter- 1 General Introduction 231.5.14 Metabolic electrolytes In metabolic therapy a pyrimidine derivative Orotic acid (82)100 is useful. To prevent heart failure of patient orate is best to synthesize pyrimidine nucleotides biologically in body as they are main constituents of DNA and RNA. . Chapter- 1 General Introduction 241.6 Conclusion