P: ISSN No. 0976-8602 RNI No.  UPENG/2012/42622 VOL.- XII , ISSUE- III July  - 2023
E: ISSN No. 2349-9443 Asian Resonance

Glycosyl Ureas as Interesting Scaffold in Medicinal Chemistry
Paper Id :  17867   Submission Date :  20/06/2023   Acceptance Date :  28/06/2023   Publication Date :  25/07/2023
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Neetu Tripathi
Assistant Professor
Chemistry Department
MKP PG College
Dehradun,Uttrakhand, India
Abstract

Synthetic urea's are known constituent of several natural products and pharmaceutical preparation. Urea derivatives are widely used in medicinal chemistry because this moiety is involved in bio chemical process in drug development. This structural component is very good building blocks in solid phase synthesis and act as precursor for synthesis of pharmacological active molecules. In present work a glycosyl urea derivative was synthesized and screened for its biological activity.
Keywords Glycosyl Urea, Isocyanate, Dichloromethane, M. Tuberculosis.
Introduction

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis and it is estimated that about 10.6 million people were affected worldwide annually and it is one of the deadliest and killer disease throughout the world. [1] WHO reports estimate about one third of world population suffering with its latent infection and therefore it has been declared as global emergency [2,3]. Therefore present study is focused on the compounds derived from carbohydrates as possible inhibitor of tuberculosis.
Aim of study

Glycosyl ureas are known to have antibacterial and antidiabetic activity. These compounds are pharmacologically important because of their biological activity. Therefore present study involves synthesis of N1, N3 substituted Glycosyl ureas for investigation of its biological activity.
Review of Literature

After covid-19 pandemic new cases  of tuberculosis have been increased globally. Multiple drug resistant (MDR) tuberculosis and its combination with HIV and mycotic infections particularly due to Candida sp. like Candida albicans, and Cryptococcus neoformans in patients with weak immune system have worsened the problem. [4-7]. Among various targets mycobacterium cell wall was chosen as unique target for development of new class of antituberculosis agents. Since the mycobacterium cell wall is composed of various glycosyl polymers like mAGP complex (mycolylated arabinogalactan peptidoglycan) complex, therefore the enzymes involved in biosynthesis of cell wall polymers are very selective target  to derive new chemotherapeutic agents. In general the  derivatives of  glycosyl urea  particularly with respect to their  roles as artificial receptors are important in this respect. [8]  Many glycohybrid molecules having condensed structure of urea are known for inhibitory activity against enzymes like glycosidase, glycogen phosphorylases etc. [9, 10] Glycosidase and glycosyl transferases are two important enzymes  involved in biosynthesis of mycobacterium cell wall. Some glycosyl ureides have shown  antileishmanial  and antimycobacterial activity. [11, 12]  Limitations of the existing drugs, prolong treatment as well as emergence of resistance  has led to the scientific community to discover new chemical entities (NCE) as antitubercular agents with novel mode of action. 
Methodology

-D-xylofuran-1,5-dialdose. [15, 16] This glycosyl aldehyde on Wittig reaction with carbethoxy methylene triphenyl phosphorane or triethyl phosphonoacetate resulted into respective glycosyl olefinic ester as a mixture of E and Z isomer . The glycosyl olefinic ester on conjugate addition reaction with 1, 5 dimethylhexyl amine led to the formation of corresponding glycosyl amino ester as a mixture of diasteroisomers. [17] The major isomer was separated by column chromatography and this was used as starting material for the formation of glycosyl urea compound. Hence the synthetic strategy involves the reaction of glycosyl amino ester with benzyl isocyanate in anhydrous dichloromethane (DCM) resulted in the formation of N1, N3-substituted glycosyl urea compound as shown below in (Scheme). The compound was characterized with help of elemental analysis, IR, 1H NMR, 13C NMR and MS FAB spectroscopy techniques. Further the synthesized compound was investigated for its biological activity against M. tuberculosis. Such compounds attracts the attention of scientific community to develop pharmacologically active compounds such as antibacterial, antifungal, and anti-inflammatory compounds. [18]a-D-glucofuranose which on oxidation with sodium metaperiodate yielded 3-O-methyl-1,2-O-isopropylidene- a-D-glucofuranose in good yield as shown in scheme. [13, 14] The later on methylation with methyl iodide and selective deprotection gave 3-O-methyl-1,2- O-isopropylidene- aThe glycosyl ureas have been synthesized as possible inhibitors of mycobacterium cell wall polymers. Sugar based complex molecules like glycosidase, glycosyl transferase and enzymes responsible for mycolic acid biosynthesis have been taken into consideration. Glycohybrid compounds are a new class of molecules of great medicinal value and are very important in design and development of novel class of antimycobacterial agents. The synthesized compound was screened for its biological activity against Mycobacterium tuberculosis. The synthesis of glycosyl urea compound starts with easily available D-glucose which on protection with acetone in presence of sulphuric acid followed by methylation gives 1,2,5,6,-di-O-isopropyledene-
Analysis


Experimental:

Ethyl-[(1R, 2R, 3S, 4S, 5S)-5-{N3-benzyl-N1-(1, 5-dimethylhexyl)-5, 6-dideoxy-1, 2-O- isopropylidene-3-O-methyl-1-ureidyl}-1, 4-heptofuranos-5-yl]-uronoate :

This glycosyl  urea compound was obtained by the reaction of glycosyl amino ester  (1.5 g, 3.74 mmol) on benzyl isocyanate (0.46 mL, 3.74 mmol) in solvent dry dichloromethane  for 6-8 hours . After completion of reaction the crude product obtained was dried and weighed. The desired compound was purified by column chromatography over SiO2 using the solvent gradient of hexane:ethyl acetate (4:1) as eluent which afforded the glycosyl urea compound as colorless foam. Yield (1.38g, 91%), [ɑ]D25 -25 (c 0.15, CH3OH); MS FAB m/z = 535 [M+H]+; IR (neat): vmax cm-1 3371 (NH), 2930 (CH), 1730 (C=O), 1639 (NC=O); 1H NMR (CDCl3, 200 MHz) δ =7.29 (m, 5H, Ar-H), 5.83 (d, J = 3.7 Hz, 1H, H-1), 4.51 (d, J = 3.7 Hz, 1H, H-2), 4.39 (d, J = 5.38 Hz, NCH₂Ph), 4.10 (m, 3H, H-4 and OCH2CH3), 3.19 (d, J = 3.0 Hz, 1H, H-3), 3.17 (s, 3H, OCH3), 3.10 (m, 1H, H-5), 2.80 (m, 1H, H-6A), 2.67 (m, 1H H-6B), 1.55 (d, 3H, NCH(CH3)), 1.47 and 1.34 [each s, each 3H, C(CH3)2], 1.30 (m, 10H, OCH2CH3 and CH₂ s and CH(CH3)2). 0.86 (d, J = 6.5 Hz, 6H, CH(CH3)2); 13C NMR (CDCl3, 50 MHz): δ=172.4 (OC=O); 158.5 (NC=O); 140.4 (Ar-C); 128.7, 128.0, 127.9, 127.2, 127.1 (Ar-CH); 112.2 [>C(CH3)2]: 105.1 (C-1); 84.5 (C-2): 81.2 (C-4): 81.0 (C-3); 61.1 (OCH2CH3): 57.7 (OCH3): 57.5 (C-5), 45.1 (NCH2Ph), 35.9 (C-6); 36.6, 30.7 (-CH₂’s), 28.3 (NCH); 27.1, 26.5 [>C(CH3)2]: 25.7 (- CH2CH(CH3)2); 23.0 (CH(CH3)2); 20.2, 19.4 (CH(CH3)2); 14.5 (OCH2CH3); Elemental Analysis for C29H46N2O7: C, 65.16; H, 8.61; N, 5.24; Found: C, 65.44; H, 9.01; N, 5.63%.

Bioevaluation:                                                               

The synthesized glycosyl urea compound [ Ethyl-[(1R, 2R, 3S, 4S, 5S)-5-{N3-benzyl-N1-(1, 5-dimethylhexyl)-5, 6-dideoxy-1, 2-O- isopropylidene-3-O-methyl-1-ureidyl}-1, 4-heptofuranos-5-yl]-uronoate] has been taken as test compound and our earlier reported glycosyl urea compound is taken as reference sample. Both were evaluated for  antitubercular activities against M. tuberculosis H37Ra and H37Rv. The results are depicted as shown below in Table. The bioevaluation methods used for screening of the above compound against M. tuberculosis are Micro Alamar Blue Assay and Agar Micro dilution techniques.[19, 20]

Table: Inhibitory activity of N1, N3-substituted Glycosyl Ureas

1# test compound, 2*= reference sample, MIC = Minimum Inhibitory Concentration 
Result and Discussion

The glcosyl urea compound with 1,5 dimethyl hexyl substituent at N1 position was synthesized to see the structure activity relationship. The table  shows comparative study of antitubercular activity of glycosyl ureas. The earlier  prepared compound with twelve carbon chain showed activity against the virulent strain H37Rv at MIC  12.5 µg /ml and showed inhibition against the strain H37Ra of  M. tuberculosis at MIC >25 µg /ml while the glycosyl urea compound having 1,5 dimethyl hexyl chain at N-1 position and benzyl substituent at N3 position  showed inhibition at MIC  >25 µg /ml against both the strains H37Ra and H37Rv of M. tuberculosis. Although, this test compound has shown activity to some extent and this led us to further optimize the compound for better biological activity. 
Conclusion

In conclusion it can be stated that glycosyl ureas might be useful compounds to search lead molecules against M. tuberculosis. As per earlier reported work such compounds have shown -glucosidase inhibitory activity and their transformation in C- nucleosides shows their potential in the field of pharmaceuticals and medicinal chemistry. Author thanks to medicinal and process chemistry division of CDRI for all experimental work and biological activity.
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