SYNTHESIS AND MOLECULAR DOCKING STUDY OF BIS-THIOBARBITURATE DERIVATIVES AS EFFECTIVE INHIBITORS OF BETA-GLUCURONIDASE

Year 2019, , 32 - 36, 01.06.2019

Hayat Ullah Fahad Khan Fazal Rahim Zia Ur Rehman Muhammad Taha Abdul Wadood Fawad Ahmad Zainul Wahab Imad Uddin Khalid Zaman

https://doi.org/10.5281/zenodo.3576583

Abstract

Bis-thiobarbiturate derivatives 1-15 have been synthesized and evaluated for their in vitro βglucuronidase inhibitory potential. The structures of all compounds were confirmed throughspectroscopic techniques such as EI-MS and HNMR. Compounds 13 IC50 = 29.42 ± 0.61µM showed potent β-glucuronidase inhibitory potential better than the standard inhibitor D-saccharicacid 1, 4 lactone, IC50 = 48.4 ± 1.25 µM . The compounds 2 IC± 0.22 µM , 4 IC50 = 55.12 ± 1.13µM and 9 IC50 = 49.84 ±1.46µM showed b-glucuronidaseinhibitory potential comparable to the standard inhibitor. Compounds 1 IC50 = 68.45 ± 0.33 µM , 5 IC50 = 61.18 ± 1.42µM , 6 IC50 = 92.57 ±2.80 µM , 7 IC50 = 61.27 ± 0.45 µM , 8 IC50 = 62.85 ±0.79µM , and 12 IC50 = 77.56 ± 1.32µM also showed good inhibitory potential. The remainingcompounds are found to be completely inactive. The structure-activity relationship was establishedfor these compounds. This study identified a novel class of β-glucuronidase inhibitors

Keywords

Organic Synthesis, Molecular Docking Studies, Thiobarbituric Acid, β-glucuronidaseInhibition, Thiobarbiturate

References

• Alimmari, Adel SA; Marinkovi'c Aleksandar D; Mijin, Duvsan; Valentic, Natasa V; Todorovi'c Nina; Uvs'cumli'c Gordana (2010). Synthesis, structure and solvatochromic properties of 3- cyano-4, 6-diphenyl-5-(3-and 4-substituted phenylazo)-2- pyridones , Journal of the Serbian Chemical Society, 75, 1019-1032
• Boyland, E; Gasson, JE; Williams, DC (1957). Enzyme activity in relation to cancer: The urinary $beta$-glucuronidase activity of patients suffering from malignant disease , British journal of cancer, 11, 120
• Essa, Fadhel Omran; Kadhum, Kadhum Jwad; Abbas, A; Drea, Ali (2012). Estimation of transition state and Synthesis of Barbituric Acid with their derivatives of 1, 3, 4-Thiadiazole , Journal of Applicable Chemistry, 1, 344-351
• Goldin, Barry R; Gorbach, Sherwood L (1976). The relationship between diet and rat fecal bacterial enzymes implicated in colon cancer , Journal of the National Cancer Institute, 57, 371-375
• Gonick, Harvey C; Kramer, Herbert J; Schapiro, Arthur E (1973). Urinary ss-glucuronidase activity in renal disease , Archives of Internal Medicine, 132, 63-69
• Hradec, E; Petvr'ik, R; Pezlarov'a J (1965). The activity of $beta$- glucuronidase in cases of bladder neoplasms , The Journal of urology, 94, 430-435
• Jain, Sanjeev; Drendel, William B; Chen, Zhi-wei; Mathews, F Scott; Sly, William S; Grubb, Jeffrey H (1996). Structure of human $beta$-glucuronidase reveals candidate lysosomal targeting and active-site motifs , Nature structural biology, 3, 375
• Khan, Khalid Mohammed; Ali, Muhammad; Farooqui, Tanveer Ahmad; Khan, Momin; Taha, Muhammad; Perveen, Shahnaz (2009). An improved method for the synthesis of 5-arylidene barbiturates using BiCl3 , J. Chem. Soc. Pak, 31, 823
• Kidwai, Mazaahir; Thakur, Ruby; Mohan, Richa (2005). Ecofriendly synthesis of novel antifungal (thio) barbituric acid derivatives , Acta Chim Slov, 52, 88-92
• Plum, C. (1967). Beta-glucuronidase activity in serum, cerebrospinal fluid and urine in normal subjects and in neurological and mental patients , Enzymologia biologica et clinica, 8, 97-112
• Rahim, Fazal; Ali, Muhammad; Ullah, Shifa; Rashid, Umer; Ullah, Hayat; Taha, Muhammad; Javed, Muhammad Tariq; Rehman, Wajid; Khan, Aftab Ahmad; Abid, Obaid Ur Rahman; others (2016). Development of bis-thiobarbiturates as successful urease inhibitors and their molecular modeling studies , Chinese Chemical Letters, 27, 693-697
• Rahim, Fazal; Malik, Fazal; Ullah, Hayat; Wadood, Abdul; Khan, Fahad; Javid, Muhammad Tariq; Taha, Muhammad; Rehman, Wajid; Rehman, Ashfaq Ur; Khan, Khalid Mohammed (2015). Isatin based Schiff bases as inhibitors of $alpha$-glucosidase: Synthesis, characterization, in vitro evaluation and molecular docking studies , Bioorganic chemistry, 60, 42-48
• Ralhan, NK; Sachdev, HS (1960). Synthesis of Barbituric Acid Derivatives , J. Sci., Ind. Res, 19, 215-218
• Ronald, Allan R; Silverblatt, Frederic; Clark, Hugh; Cutler, Ralph E; Turck, Marvin (1971). Failure of urinary beta-glucuronidase activity to localize the site of urinary tract infection , Applied and environmental microbiology, 21, 990-992
• Schapiro, Arthur; Paul, Wellington; Gonick, Harvey (1968). Urinary beta-glucuronidase in urologic diseases of the kidneys , The Journal of urology, 100, 146-157
• Singh, V; Khanna, R; Srivastava, VK; Palit, G; Shanker, K (1992). Synthesis and pharmacological evaluation of some phenothiazines as antidepressants , Arzneimittel-Forschung, 42, 277-280
• Sperker, Bernhard; Backman, Janne T; Kroemer, Heyo K (1997). The role of $beta$-glucuronidase in drug disposition and drug targeting in humans , Clinical pharmacokinetics, 33, 18-31
• Srivastava, VK; Kumar, Ashok; others (2004). Synthesis of some newer derivatives of substituted quinazolinonyl-2- oxo/thiobarbituric acid as potent anticonvulsant agents , Bioorganic & medicinal chemistry, 12, 1257-1264
• Weissmann, Gerald; Zurier, Robert B; Spieler, Paul J; Goldstein, Ira M (1971). Mechanisms of lysosomal enzyme release from leukocytes exposed to immune complexes and other particles , Journal of Experimental Medicine, 134, 149-165
• Zuccarello, Felice; Buemi, Giuseppe; Gandolfo, Concetta; Contino, Annalinda (2003). Barbituric and thiobarbituric acids: a conformational and spectroscopic study , Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 59, 139-151