Synthesis and In Vitro Enzymatic Studies of New 3-Aryldiazenyl Indoles as Promising Helicobacter pylori IMPDH Inhibitors

Author(s): Sachin Jangra , Gayathri Purushothaman , Kapil Juvale , Srimadhavi Ravi , Aishwarya Menon , Vijay Thiruvenkatam , Sivapriya Kirubakaran* .

Journal Name: Current Topics in Medicinal Chemistry

Volume 19 , Issue 5 , 2019

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Abstract:

Background & Objective: Helicobacter pylori infection is one of the primary causes of peptic ulcer followed by gastric cancer in the world population. Due to increased occurrences of multi-drug resistance to the currently available antibiotics, there is an urgent need for a new class of drugs against H. pylori. Inosine 5′-monophosphate dehydrogenase (IMPDH), a metabolic enzyme plays a significant role in cell proliferation and cell growth. It catalyses guanine nucleotide synthesis. IMPDH enzyme has been exploited as a target for antiviral, anticancer and immunosuppressive drugs. Recently, bacterial IMPDH has been studied as a potential target for treating bacterial infections. Differences in the structural and kinetic parameters of the eukaryotic and prokaryotic IMPDH make it possible to target bacterial enzyme selectively.

Methods: In the current work, we have synthesised and studied the effect of substituted 3-aryldiazenyl indoles on Helicobacter pylori IMPDH (HpIMPDH) activity. The synthesised molecules were examined for their inhibitory potential against recombinant HpIMPDH.

Results: In this study, compounds 1 and 2 were found to be the most potent inhibitors amongst the database with IC50 of 0.8 ± 0.02µM and 1 ± 0.03 µM, respectively.

Conclusion: When compared to the most potent known HpIMPDH inhibitor molecule C91, 1 was only four-fold less potent and can be a good lead for further development of selective and potent inhibitors of HpIMPDH.

Keywords: Helicobacter pylori, Inosine 5 ′-monophosphate dehydrogenase (IMPDH), Indole, Azo compounds, Enzymatic studies, Bacteria.

[1]
Hu, Y.; Zhang, M.; Lu, B.; Dai, J. Helicobacter pylori and Antibiotic Resistance, A Continuing and Intractable Problem. Helicobacter, 2016, 21(5), 349-363.
[http://dx.doi.org/10.1111/hel.12299] [PMID: 26822340]
[2]
Kusters, J.G.; van Vliet, A.H.M.; Kuipers, E.J. Pathogenesis of Helicobacter pylori infection. Clin. Microbiol. Rev., 2006, 19(3), 449-490.
[http://dx.doi.org/10.1128/CMR.00054-05] [PMID: 16847081]
[3]
Moss, S.F. The Clinical Evidence Linking Helicobacter pylori to Gastric Cancer. Cell. Mol. Gastroenterol. Hepatol., 2016, 3(2), 183-191.
[http://dx.doi.org/10.1016/j.jcmgh.2016.12.001] [PMID: 28275685]
[4]
Park, J.Y.; Dunbar, K.B.; Mitui, M.; Arnold, C.A.; Lam-Himlin, D.M.; Valasek, M.A.; Thung, I.; Okwara, C.; Coss, E.; Cryer, B.; Doern, C.D. Helicobacter pylori Clarithromycin Resistance and Treatment Failure Are Common in the USA. Dig. Dis. Sci., 2016, 61(8), 2373-2380.
[http://dx.doi.org/10.1007/s10620-016-4091-8] [PMID: 26923948]
[5]
Jenks, P.J.; Edwards, D.I. Metronidazole resistance in Helicobacter pylori. Int. J. Antimicrob. Agents, 2002, 19(1), 1-7.
[http://dx.doi.org/10.1016/S0924-8579(01)00468-X] [PMID: 11814762]
[6]
Mégraud, F. The challenge of Helicobacter pylori resistance to antibiotics: the comeback of bismuth-based quadruple therapy. Therap. Adv. Gastroenterol., 2012, 5(2), 103-109.
[http://dx.doi.org/10.1177/1756283X11432492] [PMID: 22423259]
[7]
Sintchak, M.D.; Fleming, M.A.; Futer, O.; Raybuck, S.A.; Chambers, S.P.; Caron, P.R.; Murcko, M.A.; Wilson, K.P. Structure and mechanism of inosine monophosphate dehydrogenase in complex with the immunosuppressant mycophenolic acid. Cell, 1996, 85(6), 921-930.
[http://dx.doi.org/10.1016/S0092-8674(00)81275-1] [PMID: 8681386]
[8]
Hedstrom, L. NIH Public Access. Chem. Rev., 2010, 109, 2903-2928.
[http://dx.doi.org/10.1021/cr900021w] [PMID: 19480389]
[9]
Hedstrom, L.; Liechti, G.; Goldberg, J.B.; Gollapalli, D.R. HHS Public Access. Curr. Med. Chem., 2016, 18, 1909-1918.
[http://dx.doi.org/10.2174/092986711795590129] [PMID: 21517780]
[10]
Gollapalli, D.R.; Macpherson, I.S.; Liechti, G.; Gorla, S.K.; Goldberg, J.B.; Hedstrom, L. Structural determinants of inhibitor selectivity in prokaryotic IMP dehydrogenases. Chem. Biol., 2010, 17(10), 1084-1091.
[http://dx.doi.org/10.1016/j.chembiol.2010.07. 014] [PMID: 21035731]
[11]
Kunz, P.; Sa, H.; Depeweg, D. Overexpression of Inosine 5 9 -Monophosphate Dehydrogenase Type II Mediates Chemoresistance to Human Osteosarcoma Cells. PLoS One, 2010, 5.
[http://dx.doi.org/10.1371/journal.pone.0012179]
[12]
Shah, C.P.; Kharkar, P.S. Discovery of novel human inosine 5′-monophosphate dehydrogenase 2 (hIMPDH2) inhibitors as potential anticancer agents. Eur. J. Med. Chem., 2018, 158, 286-301.
[http://dx.doi.org/10.1016/j.ejmech.2018.09.016] [PMID: 30223117]
[13]
Shah, C.P.; Kharkar, P.S. Newer human inosine 5′-monophosphate dehydrogenase 2 (hIMPDH2) inhibitors as potential anticancer agents. J. Enzyme Inhib. Med. Chem., 2018, 33(1), 972-977.
[http://dx.doi.org/10.1080/14756366.2018.1474211] [PMID: 29792360]
[14]
Gorla, S.K.; Kavitha, M.; Zhang, M.; Liu, X.; Sharling, L.; Gollapalli, D.R.; Striepen, B.; Hedstrom, L.; Cuny, G.D. Selective and potent urea inhibitors of cryptosporidium parvum inosine 5′-monophosphate dehydrogenase. J. Med. Chem., 2012, 55(17), 7759-7771.
[http://dx.doi.org/10.1021/jm3007917] [PMID: 22950983]
[15]
Makowska-Grzyska, M.; Kim, Y.; Gorla, S.K.; Wei, Y.; Mandapati, K.; Zhang, M.; Maltseva, N.; Modi, G.; Boshoff, H.I.; Gu, M.; Aldrich, C.; Cuny, G.D.; Hedstrom, L.; Joachimiak, A. Mycobacterium tuberculosis IMPDH in Complexes with Substrates, Products and Antitubercular Compounds. PLoS One, 2015, 10(10), e0138976.
[http://dx.doi.org/10.1371/journal.pone.0138976] [PMID: 26440283]
[16]
Sahu, N.U.; Singh, V.; Ferraris, D.M.; Rizzi, M.; Kharkar, P.S. Hit discovery of Mycobacterium tuberculosis inosine 5′-monophosphate dehydrogenase, GuaB2, inhibitors. Bioorg. Med. Chem. Lett., 2018, 28(10), 1714-1718.
[http://dx.doi.org/ 10.1016/j.bmcl.2018.04.045] [PMID: 29699922]
[17]
Wei, Y.; Yu, R.; Modi, G.; Hedstrom, L. Inhibition of IMPDH from Bacillus anthracis: Mechanism revealed by pre-steady state kinetics. Biochemistry, 2017, 55, 5279-5288.
[http://dx.doi.org/ 10.1021/acs.biochem.6b00265] [PMID: 27541177]
[18]
Sahu, N.U.; Purushothaman, G.; Thiruvenkatam, V.; Kharkar, P.S. Design, synthesis, and biological evaluation of Helicobacter pylori inosine 5′-monophosphate dehydrogenase (HpIMPDH) inhibitors. Drug Dev. Res., 2018.
[http://dx.doi.org/10.1002/ddr.21467] [PMID: 30381846]
[19]
Juvale, K.; Purushothaman, G.; Singh, V.; Shaik, A.; Ravi, S.; Thiruvenkatam, V.; Kirubakaran, S. Identification of selective inhibitors of Helicobacter pylori IMPDH as a targeted therapy for the infection. Sci. Rep., 2019, 9(1), 190.
[http://dx.doi.org/10.1038/s41598-018-37490-x] [PMID: 30655593]
[20]
Tsuji, T.; Takashima, H.; Takeuchi, H.; Egawa, T.; Konaka, S. Molecular structure and torsional potential of trans-azobenzene. A gas electron diffraction study. J. Phys. Chem. A, 2001, 105, 9347-9353.
[http://dx.doi.org/10.1021/jp004418v]
[21]
Piste, P.B.; Indalkar, D.P.; Zambare, D.N.; Mundada, P.S. Academic Sciences. Int. J. Chem. Reserach, 2012, 3, 4.
[22]
Drobnica, L.; Zemanová, M.; Nemec, P.; Antos, K.; Kristián, P.; Martvon, A.; Závodská, E. Antifungal activity of isothiocyanates and related compounds. 3. Derivatives of biphenyl, stilbene, azobenzene, and several polycondensed aromatic hydrocarbons. Appl. Microbiol., 1968, 16(4), 582-587.
[PMID: 5647516]
[23]
Kim, Y.; Phillips, J.A.; Liu, H.; Kang, H.; Tan, W. Using photons to manipulate enzyme inhibition by an azobenzene-modified nucleic acid probe. Proc. Natl. Acad. Sci. USA, 2009, 106(16), 6489-6494.
[http://dx.doi.org/10.1073/pnas.0812402106] [PMID: 19359478]
[24]
Lee, S.H.; Moroz, E.; Castagner, B.; Leroux, J.C. Activatable cell penetrating peptide-peptide nucleic acid conjugate via reduction of azobenzene PEG chains. J. Am. Chem. Soc., 2014, 136(37), 12868-12871.
[http://dx.doi.org/10.1021/ja507547w] [PMID: 25185512]
[25]
Yao, C.; Wang, P.; Li, X.; Hu, X.; Hou, J.; Wang, L.; Zhang, F. Near-Infrared-Triggered Azobenzene-Liposome/Upconversion Nanoparticle Hybrid Vesicles for Remotely Controlled Drug Delivery to Overcome Cancer Multidrug Resistance. Adv. Mater., 2016, 28(42), 9341-9348.
[http://dx.doi.org/10.1002/adma.201503799] [PMID: 27578301]
[26]
Phillips, J.A.; Liu, H.; Donoghue, M.B.O.; Xiong, X.; Wang, R.; You, M.; Sefah, K.; Tan, W. Using Azobenzene Incorporated DNA Aptamers to Probe Molecular Binding Interactions. 2011, 282-288.
[http://dx.doi.org/10.1021/bc100402p]
[27]
Ferreira, R.; Nilsson, J.R.; Solano, C.; Andréasson, J.; Grøtli, M. Design, Synthesis and Inhibitory Activity of Photoswitchable RET Kinase Inhibitors. Sci. Rep., 2015, 5, 9769.
[http://dx.doi.org/10.1038/srep09769] [PMID: 25944708]
[28]
Runtsch, L.S.; Barber, D.M.; Mayer, P.; Groll, M.; Trauner, D.; Broichhagen, J. Azobenzene-based inhibitors of human carbonic anhydrase II. Beilstein J. Org. Chem., 2015, 11, 1129-1135.
[http://dx.doi.org/10.3762/bjoc.11.127] [PMID: 26199669]


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VOLUME: 19
ISSUE: 5
Year: 2019
Page: [376 - 382]
Pages: 7
DOI: 10.2174/1568026619666190227212334
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