44. Designing, Synthesis and Biological Evaluation of some 5-mercapto Pyrimidine Derivatives

Rajkumar Mohanta and Susant Kumar Sahu
University Dept. of Pharmaceutical Science, Utkal University, Vani Vihar, Bhubaneswar, Odisha-751004, India
Corresponding Author: Rajkumar Mohanta, E-mail: [email protected]
Received:28 October 2012 Accepted:14 November 2012
Citation: Rajkumar Mohanta1 and Susant Kumar Sahu1 “Designing, Synthesis and Biological Evaluation of some 5-mercapto Pyrimidine Derivatives” Int. J. Drug Dev. & Res., October-December 2012, 4(4):352-358. doi: doi number
Copyright: © 2012 IJDDR, Rajkumar Mohanta et al. This is an open access paper distributed under the copyright agreement with Serials Publication, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract

The pyrimidine derivatives are the hetero cyclic compounds with having potent biological activities such as antibacterial, anti-inflammatory and analgesic,, antifungal and antihypertensive.The 5- marcapto pyrimidine moiety was synthesized by the cyclo condensation reaction between substituted thiazolidin-4-ones moiety and thiourea after insilico modeling with the target molecules (receptors like-3GI9,3FHU,4AE5 and 4COX).The energy minimization ,bond lengths and bond angles of the synthesized compounds were done in Argus Lab-5.3 and the docking results were performed by Hex-6.3 software with macro target molecules. These compounds were screened for their antibacterial and anti inflammatory activities. The zone of inhibition of these compounds was promising as compared to the standard while the anti inflammatory activity was done by protein denaturing method.

Keywords

5-marcapto pyrimidine, E-total values, energy minimization, anti bacterial and Anti inflammatory activities.

Introduction

Inflammation is a common disease and life threatening in extreme condition of allergic, autoimmune disease and rejection of transplanted organs. As per the literature review pyrimidine moiety was found to have diverse biological activities like antimicrobial1, anti-inflammatory2,3, analgesic4, antihypertensive5, antifungal6 etc. so it was planned to be synthesized a novel series of 5-marcapto pyrimidine derivatives after minimization of energy in Argus lab-4.0.1 and the docking results these compounds with targeted molecules(receptors) were calculated by using Hex-6.3 docking software7 . The receptors like, antibacterial ( E.coli-3GI9, S.aureus- 3FHU and S.typhi-4AE5) and antiinflammatory( 4COX) were derived from protein data bank (RCBS). All the synthesized compounds were screened against three microorganisms and the zone of inhibition was compared with standard drug, ciprofloxacin. The anti-inflammatory activity of these compounds were observed in UV spectrophotometry (660nm) by using bovine serum albumin (protein denaturation method)8 with compaired to standard drug Indomethacin.

Materials and Method

· Drawing of these structures, energy minimization and docking of 5-marcapto pyrimidine were done by using Chem schetch, Argus lab-4.o.1 and Hex-6.3 respectively.
· The entire chemicals were supplied by S. D. Fine Chem. (Mumbai), Finar Chem. Ltd (Ahmedabad) and Loba Chemie. Pvt. Ltd. (Mumbai).
· Melting points were determined by open tube capillary method and were uncorrected.
· Purity of compounds were checked by thin layer chromatography (TLC) on silicagel-G in solvent system hexane-ethyl acetate (1:1) and the spots were located under iodine vapours and UV light.
· IR spectra of all compounds were recorded on FT-IR 8400S Shimadzu spectrophotometer using KBr.
· Mass spectra were obtained using 2010EV LCMS Shimadzu instrument.
Synthetic procedure of 1-(substituted phenyl)-2-(substituted phenyl) Imine (Schiff bases)9 :
An equimolar (0.02mole) mixture of aromatic primary amines and aromatic aldehydes were refluxed in 40ml of dry ethanol for 18 hours. The excess of ethanol was then distilled off under reduced pressure and the resulting solid were washed with ethanol, followed by dry ether. The compounds 1(a1- a3, b1-b3) were dried and recrystallized from benzene. The yield of the compounds were found 85-95 % and the sharp melting point were obtained from all the compounds.
Synthetic procedure of 2-(substituted phenyl)-3-(substituted phenyl) thiazolidin-4- ones9:
An equimolar (0.02 mole) mixture of schiffs bases and thioglycolic acid were refluxed for 18 hours in dry benzene. Then the excess benzene was distilled off under reduced pressure and the whole content was poured over the crushed ice and centrifuged. The resulting solid were washed with ice cold saturated solution of biocarbonate followed by distilled water. Then the compounds 2(a1-a3, b1-b3) was dried and recrystallized from ethanol. Approximately 80-90% of yield of the compounds were found.
Synthetic procedure of 2-(substituted phenyl)-3-(substituted phenyl)-5-(substituted bezyilidine) thiazolidin-4-ones9:
An equimolar(0.01 mole) mixture of 4- thiazolidinones 2(a1-a3, b1-b3), aromatic aldehydes and anhydrous sodium acetate(0.082gm) in glacial acetic acid was refluxed for 3hours. Then the reaction mixture was concentrated, cooled and poured into ice cold water. The solid crystal was separated by filtration and the filtrate was washed with water, dried and recrystalized from glacial acetic acid. All these compounds 3(a1-a3, b1-b3) have approximately 70-80% of yield, melting point were shown in table- 02. The spectral data of these compounds (IR, 1HNMR &MS) were shown in table- 4.
Synthetic procedure of 2-(substituted phenyl)-3-(substituted phenyl)-7-(substituted phenyl) -2, 3, 7, 7a-tetrahydro[1, 3] thiazolo [4, 5d ]-5-mercapto pyrimidine10
An equimolar(0.001 mole) mixture of step-3 3(a1-a3, b1-b3,) and thiourea was dissolved in 50 ml of ethanol. The NaOH was dissolved in minimum quantity of water and added to it. Then the mixture was refluxed for 6 hours and the whole content mixture was poured into the cold water. Thus the solid crystalline was separated by filtration, thoroughly with water ,dried and recrystaline from ethanol. Approximately the compounds 4(a1-a3, b1- b3,c2) have 60-70% of yield and melting points were shown in the table-3. The spectral data(IR, 1HNMR and MS) was given in table-5 and the biological screening of these final compounds 4(a1-a3, b1-b3,) were shown in tables-6 &7.

Pharmacological Screening

Antibacterial activity:

All the synthesized compounds were screened for antibacterial activity by cup plat method. The concentration100μg / ml of the compounds were prepared as a stock solution by using DMF solution. The standard drug ciprofloxacin of concentration 20 μg /ml was prepared in distill water and determined the zone of inhibition. As compared to the standard, the synthesized compounds were shown promising inhibition activity against the micro organisms like E.coli,S.aureus and S.typhi . Than it was observed that the antibacterial activity was determined by both Invitro and Insilco methods parallel .The result revealed that these 5- mercapto pyrimidine derivatives can be used as an antimicrobial agent.The zone of inhibition of the compounds were shown in table-5.

Anti-inflammatory activity:

All the synthesized compounds 4(a1-3, b1-3) were screened by inhibition of protein denaturation method.

Method 8:

The reaction mixtures (0.5 mL) consisted of 0.45 ml bovine serum albumin (5% aqueous solution) and 0.05 ml of synthesized compound (100 μg/mL of final volume). pH was adjusted at 6.3 using a small amount of 1 N HCI. The samples were incubated at 37°C for 20 min and then heated at 57°C for 3 min. After cooling the samples, 2.5 mL phosphate buffer saline (pH 6.3) was added to each tube. Turbidity was measured spectrophotometrically at 660 nm. For control tests 0.05 mL distilled water was used instead of synthesized compound while product control tests lacked bovine serum albumin.

Results and discussion

• Synthesized compounds were screened for antibacterial activity by zone of inhibition and observed that 4a2, 4a3, 4b2 and 4b3 have shown good activities against the three micro organisms as compared to standard.
• A series 4(a1-3, b1-3) of the compounds were also screened for in vitro anti-inflammatory activity by inhibition of bovine serum albumine denaturation and shown that the compound 4b2 has best inhibition percentage of denaturation of bovine as compared to standard.

ACKNOWLEDGEMENT

The authors are grateful to the authorities of University Department of Pharmaceutical Sciences, Utkal University, Bhubaneswar and Institute of Pharmacy and Technology, Salipur, Cuttack, Orissa, India for providing the necessary facility to carryout this research work. We are also thankful to Dr. Sagar Mishra,UDPS, Bhubaneswar,Utkal University and Dr.Mrityunjay Banerjee,IPT,Salipur,Cuttack, India for valuable suggestions.

Conflict of Interest

NIL

Source of Support

NONE

Tables at a glance

Table icon Table icon Table icon Table icon
Table 1 Table 2 Table 3 Table 4
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Table 5 Table 5a Table 6
 
 

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