Substituted Carbazoles – A New Class of Anthelmintic Agent
David Rennison A D , Stephanie M. Gueret A , Olivia Laita A , Ross J. Bland B , Ian A. Sutherland B , Ian K. Boddy C and Margaret A. Brimble A D
+ Author Affiliations
- Author Affiliations
A School of Chemical Sciences, University of Auckland, Auckland, New Zealand.
B AgResearch Limited, Hopkirk Institute, Corner University Avenue and Library Road, Palmerston North, New Zealand.
C ParaCo Technologies Limited, Hamilton, New Zealand.
D Corresponding authors. Email: d.rennison@auckland.ac.nz; m.brimble@auckland.ac.nz
Australian Journal of Chemistry 69(11) 1268-1276 https://doi.org/10.1071/CH16169
Submitted: 18 March 2016 Accepted: 28 April 2016 Published: 30 May 2016
Abstract
A series of novel carbazoles were synthesized based on structural modifications to lead carbazole 1 (EC100 = 2.5 μM against Haemonchus contortus in vitro), which was revealed in a small molecule screening program as a potentially promising platform for the development of new anthelmintic drugs. Subsequently, analogues 19, 21, 41, 42 (EC100 = 1.25 μM, all), and 39 (EC100 = 0.625 μM) were demonstrated to exhibit enhanced in vitro anthelmintic activity over the lead structure, with compound 39 also being shown to be active in vivo against Heligmosomoides polygyrus.
References
[1] D. M. Leathwick, R. B. Besier, Vet. Parasitol. 2014, 204, 44.| Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BC2czms1Wkuw%3D%3D&md5=b7f0cc2a2fc7e6b90b5021f8596315d3CAS | 24439840PubMed |
[2] P. J. Waller, Vet. Parasitol. 2006, 139, 1.
| Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD28zgs1Wjtw%3D%3D&md5=61c292ce867678933618f8b0e1f046abCAS | 16675128PubMed |
[3] N. C. Sangster, Int. J. Parasitol. 1999, 29, 115.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXhtVyksbY%3D&md5=c6f0f990f2694bf5d932e3473a7e83ecCAS | 10048824PubMed |
[4] Y. Bansal, O. Silikari, Bioorg. Med. Chem. 2012, 20, 6208.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XhsVemtrfN&md5=77dec223c325074ae1e8c32c6d2f1313CAS | 23031649PubMed |
[5] M. L. Fascio, M. I. Errea, N. B. D’Accorso, Eur. J. Med. Chem. 2015, 90, 666.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC2cXitVyksLzO&md5=a288acaf8cfec6e5f7f98d272a881068CAS | 25499987PubMed |
[6] A. Awasthi, M. Razzak, R. Al-Kassas, J. Harvey, S. Garg, Chem. Pharm. Bull. 2012, 60, 931.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XhsFWksb7P&md5=de665c2b4d57e7cf287d5738fdfd5549CAS | 22863694PubMed |
[7] E. Papadopoulos, E. Gallidis, S. Ptochos, Vet. Parasitol. 2012, 189, 85.
| Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BC38rltVeisA%3D%3D&md5=e7e7a681fbba5f91f26add536438ed0eCAS | 22503039PubMed |
[8] I. A. Sutherland, D. M. Leathwick, Trends Parasitol. 2011, 27, 176.
| Crossref | GoogleScholarGoogle Scholar | 21168366PubMed |
[9] A. Harder, G. von Samson-Himmelstjerna, Parasitol. Res. 2002, 88, 481.
| Crossref | GoogleScholarGoogle Scholar | 12107468PubMed |
[10] R. Kaminsky, P. Ducray, M. Jung, R. Clover, L. Rufener, J. Bouvier, S. S. Weber, A. Wenger, S. Wieland-Berghausen, T. Goebel, N. Gauvry, F. Pautrat, T. Skripsky, O. Froelich, C. Komoin-Oka, B. Westlund, A. Sluder, P. Maser, Nature 2008, 452, 176.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXjt1Gnu70%3D&md5=c1c181d3862075005a8c4b5100dd3c97CAS | 18337814PubMed |
[11] R. B. Besier, Trends Parasitol. 2007, 23, 21.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXhsFGltg%3D%3D&md5=3e112544e3c6ea40c4e0a14891f7a04aCAS |
[12] T. G. Geary, N. C. Sangster, D. P. Thompson, Vet. Parasitol. 1999, 84, 275.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXlt1Kmt7w%3D&md5=f110f1ec30d62f5c3ee0ce5aa8abb828CAS | 10456419PubMed |
[13] A. Rieche, H. Gross, E. Höft, Org. Synth. 1967, 47, 1.
| Crossref | GoogleScholarGoogle Scholar |
[14] A. Vilsmeier, A. Haack, Ber. Dtsch. Chem. Ges. 1927, 60, 119.
[15] A. A. Haddach, A. Kellemanb, M. V. Deaton-Rewolinskia, Tetrahedron Lett. 2002, 43, 399.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38XhtlSg&md5=8e9c5e8b6ca69bae2e4d968588e2976cCAS |
[16] H.-J. Knölker, K. R. Reddy, Chem. Rev. 2002, 102, 4303.
| Crossref | GoogleScholarGoogle Scholar | 12428991PubMed |
[17] P. Molina, P. M. Fresneda, P. Almendros, Tetrahedron 1993, 49, 1223.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK3sXisFGitb8%3D&md5=c7b5797c7e222a5fc7182fc84cbb48c6CAS |
[18] A. W. Schmidt, K. R. Reddy, H.-J. Knölker, Chem. Rev. 2012, 112, 3193.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XltFGitLw%3D&md5=4ef737d99632c0eed421ab466f74a016CAS | 22480243PubMed |
[19] Y. M. Kim, S. Yu, J. Am. Chem. Soc. 2003, 125, 1696.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXkvFKlsQ%3D%3D&md5=d4acb5bf187dff61e16dca5c32d01c83CAS | 12580584PubMed |
[20] A. W. Freeman, M. Urvoy, M. E. Criswell, J. Org. Chem. 2005, 70, 5014.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXkt1Wru7s%3D&md5=73d0763ec54faf61def6909cdd47d8feCAS | 15960500PubMed |
[21] T. Iihama, J.-M. Fu, V. Snieckus, Synthesis 1989, 184.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK3cXitVOnug%3D%3D&md5=8f36df456846e8bd197824f965ab6a4cCAS |
[22] M. Brandl, M. S. Weiss, A. Jabs, J. Suhnel, R. J. Hilgenfeld, Mol. Biol. 2001, 307, 357.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXhslSnsb4%3D&md5=e0887f70e0cc19cc2d69ac7e1781530aCAS |
[23] E. A. Meyer, R. K. Castellano, F. Diederich, Angew. Chem. Int. Ed. 2003, 42, 1210.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXivVSrtbw%3D&md5=b7331c30e0ecbb07ceda79a475ea72f2CAS |
[24] J. P. Gallivan, D. A. Dougherty, Proc. Natl. Acad. Sci. USA 1999, 96, 9459.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXlsVymsr8%3D&md5=26b5dd2a45a678a931838e867052a487CAS | 10449714PubMed |
[25] W. W. Limburg, J. F. Yanus, D. J. Williams, A. O. Goedde, J. M. Pearson, J. Polym. Sci. A1 1975, 13, 1133.
| 1:CAS:528:DyaE2MXltFGjsb8%3D&md5=17c692811731ed2631e3fbd2546986ffCAS |
[26] M. Pudlo, D. Csanyi, F. Moreau, G. Hajos, Z. Riedl, J. Sapi, Tetrahedron 2007, 63, 10320.
| Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXpvVahs7k%3D&md5=fca0a8053f0f17895a976401e53b2162CAS |
[27] G. C. Coles, C. Bauer, F. H. M. Borgsteede, S. Geerts, T. R. Klei, M. A. Taylor, P. Waller, Vet. Parasitol. 1992, 44, 35.
| Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaK3s%2FmvF2hsg%3D%3D&md5=1b87ce64877532e2bdd93b1455c44729CAS | 1441190PubMed |
