SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME NOVEL THIAZOLO[3,2-a]PYRIMIDINES

About Authors:
Shaishavi Parikh*, Arun Parikh, Vijayalakshmi Gudaparthy
Department of pharmaceutical chemistry, L. J. Institute of Pharmacy,
Ahmedabad-382210, India.
*shaishavi21@rediffmail.com

Abstract
Thiazolo[3,2-a]pyrimidine were synthesized by the reaction of the indole aldehyde with thiourea and methyl isobuterylacetate to generate thioxo pyrimidine compound which condensed to phenacyl bromide to form thiazolo[3,2-a]pyrimidine. All synthesized compounds are characterized by the IR, Mass and NMR spectroscopy and evaluated for the antibacterial and anti fungal activity by using B. cereus, S. aureus strains of Gram positiveE. coli strain of Gram negative andC.albicans strain of fungus. The compound having nitro and methoxy substituent shows significant activity in thiazolo[3,2-a]pyrimidine derivatives.

Reference Id: PHARMATUTOR-ART-1622

INTRODUCTION
The growing demand for biologically active compounds made multicomponent reactions attractive. The multicomponent condensation (MCC) approach is especially appealing as the products are formed in single step and the diversity can be readily achieved by varying the components. A variety of heterocyclic compounds can be readily assembled employing this approach as demonstrated by the synthesis of dihydropyrimidine using Biginelli reaction^1-2.

The resulting dihydropyrimidines (DHPMs) have been reported to have antibacterial³, antiviral⁴, anti-inflammatory⁵, analgesic⁶, antihypertensive as well as calcium channel blocking^7-8 and antioxidant⁹ activities. Recently, structurally simple DHPM derivative monastrol has emerged as a mitotic kinesin Eg5 motor protein inhibitor for the development of anticancer drugs¹⁰. Furthermore, the biological activity of several recently isolated marine alkaloids has also been attributed to the dihydropyrimidinone moiety in the structure. Among them the batzelladine alkaloids A and B which inhibit the binding of HIV envelope protein gp-120 to human CD4 cells are potential compounds in AIDS therapy¹¹.

Thiazoles represent useful pharmacophore with a variety of biological activities. Various substituted thiazoles have been synthesized and examined for their antifungal and their antibacterial activity. New hybrid moieties secured by linking thiazoles with pyrimidine promises to offer fascinating scaffolds¹². Thiazolo[3,2-a]pyrimidines can be prepared by the reaction between the indole aldehyde, thiourea and methyl 4-methyl-3-oxopentanoate to generate thioxo pyrimidine compound(1) which condensed to phenacyl bromide to form thiazolo[3,2-a]pyrimidine(2a-2e).

EXPERIMENTAL
All the melting points were determined in open capillaries and are uncorrected. The purity of compounds was checked by TLC on silica gel G coated glass plates. IR spectra were recorded in KBr on shimadzu FT-IR 8300 spectrophotometer; ¹H NMR spectra in CDCl₃ on a Brucker DRX-300 at 200 MHz using TMS as an internal standard. Mass spectra were determined using direct inlet probe on a GCMS-QP2010 mass spectrometer, elemental analysis were performed on a Carlo Erba EA 1108 elemental analyser.

Synthesis of methyl 1,2,3,4-tretrahydro-4-(1H-indol-3-yl)-6-isopropyl 2-thioxopyrimidine-5-carboxylate(1)
A mixture indol-3-carboxaldehyde (1.44g, 0.01M), methyl 4-methyl-3-oxopentanoate (1.42mL, 0.012M), thiourea (1.52g, 0.020M), cupric chloride dihydrated (0.85g, 0.005M)  and few drops of Conc. Hydrochloric acid was ground together for 15-20 minutes using a mortar and pastle. The initial syrupy reaction mixture solidified within 5-10 minutes. The solid was left overnight, then washed with cold water and purified and recrystallized from ethanol.

Synthesis of methyl 3-(substituted phenyl)-5-(indol-3-yl)-7-isopropyl-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate(2a-2e)
A mixture of methyl 1,2,3,4-tretrahydro-4-(1H-indol-3-yl)-6-isopropyl-2-thioxopyrimidine-5-carboxylate (2.34g, 0.01M), substituted phenacylbromide (0.01M)  and sodium acetate/glacial acetic acid  (2g/20mL) was refluxed for 5-6 hours, the completion of reaction was monitored through TLC, the content were  poured into crushed ice, the product  was isolated and recrystallised from ethanol.

SCHEME

Where, R=4-Br,4-Cl,4-OH,4-NO₂,4-OCH₃.

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RESULT

BIOLOGICAL STUDIES

Antibacterial and antifungal activity by cup plate agar diffusion method
All the compounds have been evaluated for their in vitro biological assay like antibacterial activity towards gram-positive bacteria viz., B.cereus, S.aureus, and gram-negative bacteria viz.,E.coli and antifungal activity towards c. albicans at a concentration of 100 μg. The biological activities of synthesized compounds were compared with standard drugs viz., streptomycin, tetracycline for antibacterial activity and antifungal activity was compared with miconazole.

RESULT AND DISCUSSION
The thiazolo[3,2-a]pyrimidine derivatives have been synthesized by the synthesis of the pyrimidine thione and then it was further condensed to substituted phenacylbromide. Pyrimidine thione compound have been synthesized by the Biginelli reaction, the condensation of indole aldehyde, methylisobuteryl acetate and thiourea in presence of cupric chloride and acid as catalyst by grindstone green chemical method.

It has been observed from the antimicrobial activity data that all compounds were found to be mild to moderately active against Gram positive, Gram negative and fungal strains. However, maximum activity was observed in compounds bearing R= -OCH₃ against the Gram positive strains, R= -OCH3, -NO₂ against the Gram negative strain and R= -OCH₃,-Cl against the fungi as compared to standard drug streptomycin for Gram positive, tetracycline for Gram negative and miconazole for the fungi.

ACKNOWLEDGEMENT
The authors are thankful to authorities of L. J. Institute of Pharmacy, Ahmadabad for providing the research facilities, Department of chemistry, Saurastra University, Rajkot for providing necessary IR spectra, Cadila Pharmaceuticals for providing the Mass spectra and IICT, Hyderabad for providing NMR spectra.

REFERENCES
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