Synthesis and Biological Evaluation of Some New Pyrimidines free essay sample

General Papers ARKIVOC 2008 (xi) 131-141 Synthesis and biological evaluation of some new pyrimidines via a novel chalcone series Amit R. Trivedi, Dipti K. Dodiya, Naresh R. Ravat, and Viresh H. Shah* Department of Chemistry, Saurashtra University, Rajkot (Gujarat), India, Pin-360005 E-mail: [emailprotected] com Abstract In the present investigation ethyl 2-(4-carboxyphenylazo)acetoacetate 1 on condensation with various aromatic aldehydes in ethanolic NaOH solution yielded the corresponding chalcones 2a-j. These chalcones were further reacted with urea in the presence of base in ethanol, which led to the formation of pyrimidine derivatives 3a-j. The newly synthesized heterocyles were characterized on the basis of their chemical properties and spectroscopic data. All newly synthesized compounds were evaluated for their antimycobacterial activities against Mycobacterium tuberculosis H37Rv. Keywords: Pyrimidine, antimycobacterial, Mycobacterium tuberculosis Introduction Tuberculosis (TB) is by far the most frequently encountered mycobacterial disease in the world. Although its incidence has diminished significantly in the industrially more developed countries; it remains a major public health problem in most of the developing nations. We will write a custom essay sample on Synthesis and Biological Evaluation of Some New Pyrimidines or any similar topic specifically for you Do Not WasteYour Time HIRE WRITER Only 13.90 / page Tuberculosis is still the single largest infection having a high mortality rate and 0. 1 to 0. 3 percent of the population become infected each year in the developed countries. This year, 2 million people may develop the disease and 30 million may die worldwide (as per a WHO report). It is commonly known that Mycobacterium tuberculosis has developed resistance to the majority of the existing drugs. However, powerful new anti-TB drugs with new mechanisms of action have not been developed in the last forty years. In the developing countries, the annual infection rate is 20–50 times greater than in the developed countries and its high level shows little or no downward trend. It is expected that development of new effective anti-TB drugs will bring various outcomes viz: shortening the total duration of therapy, reducing the total expenditure and treatment of multiple drug resistant tuberculosis (MDR-TB) by single dosage regiment. ,3 In pursuit of achieving this goal, our research efforts are focused on the development of novel structural moieties having antimycobacterial properties. 4,5 Chalcones have various biological activities such as cytotoxic,5 ISSN 1551-7012 Page 131 Â © ARKAT USA, Inc. General Papers ARKIVOC 2008 (xi) 131-141 antimalarial,6 antioxidant,7 tyrosinase Inhibitory,8 anti-inflammatory,9 cancer chemopreventive9 and antibacterial. 10 Several pyrimidine deri vatives have wide varieties of usages and its nucleus is also present in vitamin B2 and folic acid. Pyrimidine heterocycles possessing hydroxyl group has a unique place in medicinal chemistry,11 and also plays a vital role in biological processes12, 13 as well as synthetic drugs. 14 Pyrimidines are associated with various therapeutic activities e. g. , anti-HIV,15 anti-tubercular,16 antitumor,17 antineoplastic,18 anti-inflammatory,19 diuretic,20 antimalaria,21 cardiovascular. 22 To the best of our knowledge, there has been no previous reports of analogous pyrimidines and parent chalcones as antituberculosis agents. However, there are numerous examples of nitrogen containing heterocycles being used to treat TB, for example Clofazimine, Isoniazid and Pyrazinamide. These compounds provide structural precedence that our chalcone and pyrimidine analogues may lead to the generation of novel anti-TB therapeutics. Herein the synthesis and in vitro antimycobacterial activity of novel chalcone and pyrimidine derivatives are described. Results and Discussion Chemistry The synthesis of chalcone and pyrimidine derivatives was performed following the steps shown in Scheme-1. In the initial step, chalcones (2a-j) were synthesized by condensing 2-(4carboxyphenylazo)acetoacetate23 1 with appropriate arometic aldehydes in dilute ethanolic sodium hydroxide solution at room temperature. The compounds (3a-j) were synthesized by reacting the appropriate chalcone with urea and potassium hydroxide in ethanol. The purity of the compounds was determined by TLC and elemental analysis. Spectral data (IR, 1H-NMR, 13C NMR and Mass) of all the newly synthesized compounds were in full agreement with the proposed structures. ISSN 1551-7012 Page 132 Â © ARKAT USA, Inc. General Papers ARKIVOC 2008 (xi) 131-141 O OH O OH + R-CHO NaOH/EtOH -C2H5OH -CO2 O N N O N N CH3 ? ? R (1) O (2a-j) OC2H5 O H2N KOH/EtOH NH2 O OH N R= Phenyl, 2-Hydroxyphenyl, 4- Hydroxyphenyl, 2-Nitrophenyl, 3- Nitrophenyl, 2-Chlorophenyl, 4-Methoxyphenyl, 3-Methoxy-4-hydroxy-phenyl, Styryl, 2-Furyl, N R (3a-j) N NH OH Scheme 1 The possible mechanism involved in the formation of dihydropyrimidine derivatives (3a-j) from the respective chalcones (2a-j) is shown below. ISSN 1551-7012 Page 133 Â © ARKAT USA, Inc. General Papers ARKIVOC 2008 (xi) 131-141 R H O H2 N R R NH2 R + O KOH Conjugated addition NH +H NH R OH H2N O R OH H2N O R H NH +H H R R NH -H2O O R N H NH R OH N H O R OH2 N H O HO R N N = O Biological screening Microbiology The in vitro activities of the synthesized compounds (2a-j 3a-j) for tuberculosis inhibition against the Mycobacterium tuberculosis H37Rv (ATCC27294) strain were performed using the micro plate alamar blue assay (MABA)24 method at TAACF. Compounds exhibiting fluorescence are tested in a BACTEC-460 radiometric system25, 26 and/or broth micro dilution assay. The activities are expressed as minimum inhibitory concentration (MIC, Â µg/mL) and are summarized in Table 1. Compounds demonstrating at least 90 % inhibition were re-tested at lower concentrations to determine the actual MIC, a value defined as the lowest concentration inhibiting ? 90% of the inoculums relative to the control. Antimycobacterial activity Twenty compounds were screened for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv using a BACTEC-460 radiometric system. Among the chalcones 2a-j and pyrimidines 3a-j, compounds 3d, 3e and 3g produced the highest efficacy and exhibited ;90% inhibition at 6. 5 ? Â µg/ml in the primary screen (Table 1). Compounds 2a-j, 3a-c, 3f and 3h-j exhibited ;90% inhibition against Mycobacterium tuberculosis at 6. 25 Â µg/mL (Table 1). These antimycobacterial data clearly indicated that the presence of 2-nitro, 3-nitro and 4-methoxy substitution on chalcone produced remarkable improvements in antitubercular activity. ISSN 1551-7012 Page 134 Â © ARKAT USA, Inc. General Papers ARKIVOC 2008 (xi) 131-141 Table 1. In vitro antimyc obacterial screening data of 2a-j 3a-j Sr. No. a 2b 2c 2d 2e 2f 2g 2h 2i 2j 3a 3b 3c 3d 3e 3f 3g 3h 3i 3j R Phenyl 2-Hydroxyphenyl 4- Hydroxyphenyl 2-Nitrophenyl 3- Nitrophenyl 2-Chlorophenyl 4-Methoxyphenyl 3-Methoxy-4-hydroxy-phenyl Styryl 2-Furyl Phenyl 2-Hydroxyphenyl 4- Hydroxyphenyl 2-Nitrophenyl 3- Nitrophenyl 2-Chlorophenyl 4-Methoxyphenyl 3-Methoxy-4-hydroxy-phenyl Styryl 2-Furyl Molecular Formula C17H14N2O3 C17H14N2O4 C17H14N2O4 C17H13N3O5 C17H13N3O5 C17H13N2O3Cl C18H16N2O4 C18H16N2O5 C19H16N2O3 C15H12N2O4 C18H16N4O3 C18H16N4O4 C18H16N4O4 C18H15N5O5 C18H15N5O5 C18H15N4O3Cl C19H18N4O4 C19H18N4O5 C20H18N4O3 C16H14N4O4 MIC Â µg/mL