Design, Synthesis, and Anti-bacterial Activity of Novel Deoxycholic Acid- Amino Alcohol Conjugates

Author(s): Satyendra Mishra*, Sejal Patel.

Journal Name: Medicinal Chemistry

Volume 16 , Issue 3 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Numerous synthetic bile acid derivatives have been recognized for their various biological activities. Among these, bile acid amides have emerged as an attractive antibacterial agent. We herein illustrate the synthesis and antibacterial evaluation of deoxycholic acidamino alcohols conjugates.

Objective: Design and Synthesis of novel deoxycholic acid-amino alcohol conjugates to investigate their antibacterial activity against E. coli and S. aureus.

Methods: Novel deoxycholic acid-amino alcohol conjugates were synthesized, from conjugation of deoxycholic acid-NHS ester with amino alcohols. Various amino alcohols moieties were appended to the C24 position of deoxycholic acid to yield deoxycholic acid-amino alcohol conjugates. All the synthesized compounds were characterized by 1H NMR, 13C NMR, IR and massspectroscopy. The entire synthesized deoxycholic acid-amino alcohol conjugates were evaluated for their antibacterial activity against E. coli and S. aureus using the broth dilution method.

Results: The outcome illustrated that some of the novel deoxycholic acid-amino alcohol conjugates exhibited enhanced anti-bacterial activities. Amongst them, deoxycholic acid-amino alcohol conjugate containing (-R)-2-aminocyclohexanol (1) demonstrated promising efficacy against both strains S. aureus ATCC 25923 (MIC 15 μg/mL) and E. coli ATCC 25922 (MIC 45 μg/mL) and was identified as a lead molecule.

Conclusion: Numbers of novel deoxycholic acid-amino alcohol conjugates were synthesized and their antimicrobial activities provided useful information that the potency was strongly depending on the structures of deoxycholic acid-amino alcohol conjugates.

Keywords: Deoxycholic acid, amino-alcohol, antibacterial agent, S. Aureus, E. coli, conjugates.

[1]
a) Nonappa, Maitra, U. Unlocking the potential of bile acids in synthesis, supramolecular/materials chemistry and nanoscience. Org. Biomol. Chem., 2008, 6, 657-669.
(b) Virtanen, E.; Koleh-mainen, E. Use of bile acids in pharmacological and supramole-cular applications. Eur. J. Org. Chem., 2004,, 2004,, 3385-3399.
[2]
Stamp, D.; Jenkins, G. Bile Acids: Toxicology and Bioactivity; Royal Society of Chemistry: Cambridge, 2008, pp. 1-13.
[3]
Li, C.; Peters, A.S.; Meredith, E.L.; Allman, G.W.; Savage, P.B. Design and synthesis of potent sensitizers of gram-negative bacteria based on a cholic acid scaffolding. J. Am. Chem. Soc., 1998, 120(12), 2961-296.
[4]
Sharma, R.; Long, A.; Gilmer, J.F. Advances in bile acid medicinal chemistry. Curr. Med. Chem., 2011, 18, 4029-4052.
[5]
Mukhopadhyay, S.; Maitra, U. Chemistry and biology of bile acids. Curr. Sci., 2004, 87(12), 1666-1683.
[6]
Hofmann, A.F. The continuing importance of bile acids in liver and intestinal disease. Arch. Intern. Med., 1999, 159, 2647-2658.
[7]
Sievänen, E. Exploitation of bile acid transport systems in prodrug design. Molecules, 2007, 12(8), 1859-1889.
[8]
Tsukamoto, S.; Matsunaga, S.; Fusetani, N.; van Soest, R.W. Acanthosterol sulfates A–J: ten new antifungal steroidal sulfates from a marine sponge. Acanthodendrilla sp. J. Nat. Prod., 1998, 61, 1374-1378.
[9]
Mohamed, N.R.; Elmegeed, G.A.; Abd-ElMalek, H.A.; Younis, M. Synthesis of biologically active steroid derivatives by the utility of Lawesson’s reagent. Steroids, 2005, 70, 131-136.
[10]
Jean, M.B.; Céline, L.; Nicolas, V.; Michel, D.; Yves, L. Synthesis and antifungal activity of oxygenated cholesterol derivatives. Steroids, 2005, 70, 907-912.
[11]
Zhang, Y.L.; Li, H.Z.; Zhang, Y.J.; Jacob, M.R.; Khan, S.I.; Li, X.C.; Yang, C.R. Atropurosides A–G, newsteroidal saponins from Smilacina atropurpurea. Steroids, 2006, 71, 712-719.
[12]
Eko, W.S.; Carla, S.; Joseph, O.F.; Richard, D.G. Synthesis and antimicrobial evaluation of water-soluble, dendritic derivatives of epimeric 5α-cholestan-3-aminesand 5α-cholestan-3-yl aminoethanoates. Steroids, 2007, 72, 615-626.
[13]
Salunke, D.B.; Hazra, B.G.; Pore, V.S.; Bhat, M.K.; Nahar, P.B.; Deshpande, M.V. New steroidal dimers with antifungal and antiproliferative activity. J. Med. Chem., 2004, 47, 1591-1594.
[14]
Visbal, G.; San-Blas, G.; Maldonado, A.; Álvarez-Aular, Á.; Capparelli, M.V.; Murgich, J. Synthesis, in vitro antifungal activity and mechanism of action of four sterol hydrazone analogues against the dimorphic fungus Paracoccidioides brasiliensis. Steroids, 2011, 76, 1069-1081.
[15]
Brossard, D.; El, L.; Sebbahi, W.; Khalid, M.; Roussakis, C.; Rault, S. Synthesis of bile acid derivatives and in vitro cytotoxic activity with pro-apoptotic process on multiple myeloma (KMS-11), glioblastoma multiforme (GBM), and colonic Carcinoma (HCT-116) human cell lines. Eur. J. Med. Chem., 2010, 45, 2912-2918.
[16]
Mrózek, L.; Dvořáková, L.; Mandelová, Z.; Rárov, L.; Řezáčová, A.; Plaček, L.; Opatřilová, R.; Dohnal, J.; Paleta, O.; Král, V.; Drašar, P.; Jampílek, J. Investigation of new acyloxy derivatives of cholic acid and their esters as drug absorption modifiers. Steroids, 2011, 76, 1082-1097.
[17]
Dong, Z.; Li, Q.; Guo, D.; Shu, Y.; Polli, J.E. Pharmaceutics, drug delivery and pharmaceutical technology synthesis and evaluation of Bile Acid-Ribavirin conjugates asprodrugs to target the liver. J. Pharm. Sci., 2015, 104, 2864-2876.
[18]
Ðanić, M.; Stanimirov, B.; Pavlović, N.; Goločorbin-Kon, S.; Al-Salami, H.; Stankov, K.; Mikov, M. Pharmacological applications of bile acids and their derivatives in the treatment of metabolic syndrome. Front. Pharmacol., 2018, 9, 1382.
[19]
Popadyuk, I.I.; Salomatina, O.V.; Salakhutdinov, N.F. Modern approaches to bile acids modifications for the synthesis of compounds possessing valuable physicochemical and biological properties. Russ. Chem. Rev., 2017, 86, 388-443.
[20]
Li, C.; Peters, A.S.; Meridith, E.L.; Allman, G.W.; Savage, P.B. Incremental conversion of outer-membrane permeabilizers into potent antibiotics for gram-negative bacteria. J. Am. Chem. Soc., 1998, 120, 2961-2962.
[21]
Bavikar, S.N.; Salunke, D.B.; Hazra, B.G.; Pore, V.S.; Dodd, R.H.; Thierry, J.; Shirazi, F.; Deshpande, M.V.; Kadreppa, S.; Chattopadhyay, S. Synthesis of chimeric tetrapeptide-linked cholic acid derivatives: impending synergistic agents. Bioorg. Med. Chem. Lett., 2008, 18, 5512-5517.
[22]
Rasras, A.J.M.; Al-Tel, T.H.; Al-Aboudi, A.F.; Al-Qawasmeh, R.A. Synthesis and antimicrobial activity of cholic acid hydrazone analogues. Eur. J. Med. Chem., 2010, 45, 2307-2313.
[23]
Guan, Q.; Li, C.; Schmidt, E.J.; Boswell, J.S.; Walsh, J.P.; Allman, G.W.; Savage, P.B. Preparation and characterization of cholic acid-derived antimicrobial agents with controlled stabilities. Org. Lett., 2000, 18(2), 2837-2840.
[24]
Agarwal, D.S.; Singh, R.P.; Lohitesh, K.; Jha, P.N.; Chowdhury, R.; Sakhuja, R. Synthesis and evaluation of bile acid amides of α-cyanostilbenes as anticancer agents. Mol. Divers., 2018, 22(2), 305-321.
[25]
Hazra, B.G.; Pore, V.S.; Dey, S.K.; Datta, S.; Darokar, P.M.; Saikia, D.; Khanuja, S.P.S.; Thakur, A.P. Bile acid amides derived from chiral amino alcohols: novel antimicrobials and antifungals. Bioorg. Med. Chem. Lett., 2004, 14, 773-777.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 3
Year: 2020
Page: [385 - 391]
Pages: 7
DOI: 10.2174/1573406415666190206231002
Price: $65

Article Metrics

PDF: 13
HTML: 1