Login Register Cart 0
Generic placeholder image

Current Topics in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Computer-Assisted Design of Thiophene-Indole Hybrids as Leishmanial Agents

Author(s): Mayara Barbalho Félix, Rodrigo Santos Aquino de Araújo, Renata Priscila Costa Barros, Carlos Alberto de Simone, Raiza Raianne Luz Rodrigues, Thaís Amanda de Lima Nunes, Klinger Antonio da Franca Rodrigues, Francisco Jaime Bezerra Mendonça Junior, Eugene Muratov, Luciana Scotti and Marcus Tullius Scotti*

Volume 20, Issue 19, 2020

Page: [1704 - 1719] Pages: 16

DOI: 10.2174/1568026620666200616142120

Price: $65

Abstract

Background: Chemoinformatics has several applications in the field of drug design, helping to identify new compounds against a range of ailments. Among these are Leishmaniasis, effective treatments for which are currently limited.

Objective: To construct new indole 2-aminothiophene molecules using computational tools and to test their effectiveness against Leishmania amazonensis (sp.).

Methods: Based on the chemical structure of thiophene-indol hybrids, we built regression models and performed molecular docking, and used these data as bases for design of 92 new molecules with predicted pIC50 and molecular docking. Among these, six compounds were selected for the synthesis and to perform biological assays (leishmanicidal activity and cytotoxicity).

Results: The prediction models and docking allowed inference of characteristics that could have positive influences on the leishmanicidal activity of the planned compounds. Six compounds were synthesized, one-third of which showed promising antileishmanial activities, with IC50 ranging from 2.16 and 2.97 μM (against promastigote forms) and 0.9 and 1.71 μM (against amastigote forms), with selectivity indexes (SI) of 52 and 75.

Conclusion: These results demonstrate the ability of Quantitative Structure-Activity Relationship (QSAR)-based rational drug design to predict molecules with promising leishmanicidal potential, and confirming the potential of thiophene-indole hybrids as potential new leishmanial agents.

Keywords: QSAR, Drug design, 2-amino-thiophene, Indole, Leishmaniasis, Leishmania amazonensis.

« Previous Next »
Graphical Abstract

[1]
Brown, F.K. Chemoinformatics: What it is and how it affects drug discovery. Annu. Rep. Med. Chem., 1998, 33, 375-384.
[http://dx.doi.org/10.1016/S0065-7743(08)61100-8]
[2]
Gasteiger, J. Chemoinformatics: achievements and challenges, a personal view. Molecules, 2016, 21(2), 151.
[http://dx.doi.org/10.3390/molecules21020151] [PMID: 26828468]
[3]
Estrada, E. Spectral moments of the edge adjacency matrix in molecular graphs. 1. Definition and applications to the prediction of physical properties of alkanes. J. Chem. Inf. Comput. Sci., 1996, 36, 844-849.
[http://dx.doi.org/10.1021/ci950187r]
[4]
Tahghighi, A.; Hamzeh-Mivehroud, M.; Zeynalid, K.A.; Foroumadie, A.; Dastmalchi, S. QSAR and docking studies on the (5-nitroheteroaryl-1,3,4-thiadiazole-2-yl) piperazinyl analogs with antileishmanial activity. J. Chemometr., 2016, 30, 284-293.
[http://dx.doi.org/10.1002/cem.2789]
[5]
Félix, M.B.; de Souza, E.R.; de Lima, M.D.C.A.; Frade, D.K.G.; Serafim, V.L.; Rodrigues, K.A.D.F.; Néris, P.L.D.N.; Ribeiro, F.F.; Scotti, L.; Scotti, M.T.; de Aquino, T.M.; Mendonça Junior, F.J.B.; de Oliveira, M.R. Antileishmanial activity of new thiophene-indolehybrids: Design, synthesis, biological and cytotoxic evaluation, andchemometric studies Bioorg. Med. Chem., 2016, 24(18), 3972-3977.
[http://dx.doi.org/10.1016/j.bmc.2016.04.057] [PMID: 27515718]
[6]
Rodrigues, K.A.F.; Dias, C.N.S.; Néris, P.L.N. Rocha, Jda.C.; Scotti, M.T.; Scotti, L.; Mascarenhas, S.R.; Veras, R.C.; de Medeiros, I.A.; Keesen, Tde.S.; de Oliveira, T.B.; de Lima, Mdo.C.; Balliano, T.L.; de Aquino, T.M.; de Moura, R.O.; Mendonça Junior, F.J.; de Oliveira, M.R. 2-Amino-thiophene derivatives present antileishmanial activity mediated by apoptosis and immunomodulation in vitro. Eur. J. Med. Chem., 2015, 106, 1-14.
[http://dx.doi.org/10.1016/j.ejmech.2015.10.011] [PMID: 26513640]
[7]
Serafim, V.L.; Félix, M.B.; Silva, D.K.F.; Rodrigues, K.A.F.; Andrade, P.N.; De Almeida, S.M.V.; Dos Santos, S.A.; deOliveira, J.F.; de Lima, M.C.A. Mendonça-Junior, F.J.B.; Scotti, M.T.;de Oliveira, M.R.; de Moura, R.O. New thiophene-acridinecompounds: synthesis, antileishmanial activity, DNA binding,chemometric and molecular docking studies. Chem. Biol. Drug Design., 2018, 91, 1141-1155.
[http://dx.doi.org/10.1111/cbdd.13176]
[8]
Balaña-Fouce, R.; Reguera, R.M.; Cubría, J.C.; Ordóñez, D. The pharmacology of leishmaniasis. Gen. Pharmacol., 1998, 30(4), 435-443.
[http://dx.doi.org/10.1016/S0306-3623(97)00268-1] [PMID: 9580315]
[9]
Ferreira, M.A. Nanostructured lipid carriers containing annatto oil(Bixa orellana L.): an alternative for the treatment of cutaneousleishmaniasis. PhD thesis, Universidade Federal do Rio Grande doNorte – UFRN: Natal,. 2018.
[10]
Zulfiqar, B.; Shelper, T.B.; Avery, V.M. Leishmaniasis drug discovery: recent progress and challenges in assay development. Drug Discov. Today, 2017, 22(10), 1516-1531.
[http://dx.doi.org/10.1016/j.drudis.2017.06.004] [PMID: 28647378]
[11]
Gutiérrez-Rebolledo, G.A.; Drier-Jonas, S.; Jiménez-Arellanes, M.A. Natural compounds and extracts from Mexican medicinal plants with anti-leishmaniasis activity: An update. Asian Pac. J. Trop. Med., 2017, 10(12), 1105-1110.
[http://dx.doi.org/10.1016/j.apjtm.2017.10.016] [PMID: 29268964]
[12]
Sangi, D.P. Estratégias de síntese na descoberta de fármacos: o emprego da síntese orientada pela diversidade estrutural. Quim. Nova, 2016, 39, 995-1006.
[13]
Rodrigues, K.A.D.F.; Silva, D.K.F.; Serafim, V.L.; Andrade, P.N.; Alves, A.F.; Tafuri, W.L.; Batista, T.M.; Mangueira, V.M.; Sobral, M.V.; Moura, R.O.; Mendonça Junior, F.J.B.; Oliveira, M.R. SB-83, a 2-Amino-thiophene derivative orally bioavailable candidate for the leishmaniasis treatment. Biomed. Pharmacother., 2018, 108, 1670-1678.
[http://dx.doi.org/10.1016/j.biopha.2018.10.012] [PMID: 30372869]
[14]
Jacomini, A.P.; Silva, M.J.V.; Silva, R.G.M.; Gonçalves, D.S.; Volpato, H.; Basso, E.A.; Paula, F.R.; Nakamura, C.V.; Sarragiotto, M.H.; Rosa, F.A. Synthesis and evaluation against Leishmania amazonensis of novel pyrazolo[3,4-d]pyridazinone-N-acylhydrazone-(bi)thiophene hybrids. Eur. J. Med. Chem., 2016, 124, 340-349.
[http://dx.doi.org/10.1016/j.ejmech.2016.08.048] [PMID: 27597410]
[15]
Saini, S.; Kumar, A.; Singh, V.; Singh, R.; Dwivedi, J. Pharmacological significances of pyrimidine derivatives: a review. World J. Pharmacol. Res. Techn., 2013, 1, 9-117.
[16]
Jorgensen, W.L. Efficient drug lead discovery and optimization. Acc. Chem. Res., 2009, 42(6), 724-733.
[http://dx.doi.org/10.1021/ar800236t] [PMID: 19317443]
[17]
Consonni, V.; Todeschini, R.; Pavan, M. Structure/response correlations and similarity/diversity analysis by GETAWAY descriptors. 1. Theory of the novel 3D molecular descriptors. J. Chem. Inf. Comput. Sci., 2002, 42(3), 682-692.
[http://dx.doi.org/10.1021/ci015504a] [PMID: 12086530]
[18]
Kode srl, Dragon (Software for Molecular Descriptor Calculation)version 7.0, 2016.http://chm.kode-solutions.net available on:
[19]
Todeschini, R.; Consonni, V.; Mauri, A.; Pavan, M. Mobydigs: software for regression and classification models by genetic algorithms.Nature-inspired methods in chemometrics: genetic algorithms and artificial neural network; Elsevier: Amsterdam, 2004, pp. 141-167.
[20]
Real, F.; Vidal, R.O.; Carazzolle, M.F.; Mondego, J.M.; Costa, G.G.; Herai, R.H.; Würtele, M.; de Carvalho, L.M.; Carmona e Ferreira, R.; Mortara, R.A.; Barbiéri, C.L.; Mieczkowski, P.; da Silveira, J.F.; Briones, M.R.; Pereira, G.A.; Bahia, D. The genome sequence of Leishmania (Leishmania) amazonensis: functional annotation and extended analysis of gene models. DNA Res., 2013, 20(6), 567-581.
[http://dx.doi.org/10.1093/dnares/dst031] [PMID: 23857904]
[21]
Acuña, S.M.; Aoki, J.I.; Laranjeira-Silva, M.F.; Zampieri, R.A.; Fernandes, J.C.R.; Muxel, S.M.; Floeter-Winter, L.M. Arginase expression modulates nitric oxide production in Leishmania (Leishmania) amazonensis. PLoS One, 2017, 12(11)e0187186
[http://dx.doi.org/10.1371/journal.pone.0187186] [PMID: 29135983]
[22]
Freitas, R.F. Integration of Methods in chemoinformatics andbiocalorimetry for the design of Trypanosoma glyceraldehyde-3-phosphate dehydrogenase inhibitors, PhD Thesis, Universidade deSão Paulo: São Paulo,. 2009.
[23]
Vincendeau, P.; Gobert, A.P.; Daulouède, S.; Moynet, D.; Mossalayi, M.D. Arginases in parasitic diseases. Trends Parasitol., 2003, 19(1), 9-12.
[http://dx.doi.org/10.1016/S1471-4922(02)00010-7] [PMID: 12488215]
[24]
Das, P.; Lahiri, A.; Lahiri, A.; Chakravortty, D. Modulation of the arginase pathway in the context of microbial pathogenesis: a metabolic enzyme moonlighting as an immune modulator. PLoS Pathog., 2010, 6(6)e1000899
[http://dx.doi.org/10.1371/journal.ppat.1000899] [PMID: 20585552]
[25]
Marché, S.; Michels, P.A.; Opperdoes, F.R. Comparative study of Leishmania mexicana and Trypanosoma brucei NAD-dependent glycerol-3-phosphate dehydrogenase. Mol. Biochem. Parasitol., 2000, 106(1), 83-91.
[http://dx.doi.org/10.1016/S0166-6851(99)00204-2] [PMID: 10743613]
[26]
Morgan, H.P.; McNae, I.W.; Nowicki, M.W.; Zhong, W.; Michels, P.A.M.; Auld, D.S.; Fothergill-Gilmore, L.A.; Walkinshaw, M.D. The trypanocidal drug suramin and other trypan blue mimetics are inhibitors of pyruvate kinases and bind to the adenosine site. J. Biol. Chem., 2011, 286(36), 31232-31240.
[http://dx.doi.org/10.1074/jbc.M110.212613] [PMID: 21733839]
[27]
Micheletti, A.C.; Beatriz, A. Recent progress in the search for organic compounds with potential leishmanicidal activity. Rev. Virtual Quím., 2012, 4, 268-286.
[28]
Cruciani, G.; Pastor, M.; Guba, W. VolSurf: a new tool for the pharmacokinetic optimization of lead compounds. Eur. J. Pharm. Sci., 2000, 11(Suppl. 2), S29-S39.
[http://dx.doi.org/10.1016/S0928-0987(00)00162-7] [PMID: 11033425]
[29]
Enraf-Nonius, COLLECT Nonius BV, Delft, The Netherlands,1997–2000.
[30]
Otwinowski, Z.; Minor, W. HKL Denzo and Scalepack. in:Methods in Enzymology, 276; Carter, C.W., Jr; Sweet, R.M., Eds.; Academic Press: New York, 1997, pp. 307-326.
[31]
Sheldrick, G.M. SHELXS-97. Program for Crystal Structure Resolution; Univ. of Göttingen: Göttingen, Germany, 1997.
[32]
Farrugia, L.J. ORTEP3 for Windows. J. Appl. Cryst., 1997, 30, 565.
[http://dx.doi.org/10.1107/S0021889897003117]
[33]
Farrugia, L.S. WinGX suite for small-molecule single-crystal crystallography. J. Appl. Cryst., 1999, 32, 837-838.
[http://dx.doi.org/10.1107/S0021889899006020]
[34]
Néris, P.L.N.; Caldas, J.P.A.; Rodrigues, Y.K.S.; Amorim, F.M.; Leite, J.A.; Rodrigues-Mascarenhas, S.; Barbosa-Filho, J.M.; Rodrigues, L.C.; Oliveira, M.R. Neolignan Licarin A presents effect against Leishmania (Leishmania) major associated with immunomodulation in vitro. Exp. Parasitol., 2013, 135(2), 307-313.
[http://dx.doi.org/10.1016/j.exppara.2013.07.007] [PMID: 23891943]
[35]
Ueda-Nakamura, T.R.R.; Morgado-Díaz, J.A.; Korehisa Maza, P.; Prado Dias Filho, B.; Aparício Garcia Cortez, D.; Alviano, D.S.; Rosa, M. do S.; Lopes, A.H.; Alviano, C.S.; Nakamura, C.V. Antileishmanial activity of Eugenol-rich essential oil from Ocimum gratissimum. Int. J. Parasitol., 2006, 55, 99-105.
[http://dx.doi.org/10.1016/j.parint.2005.10.006]
[36]
Shio, M.T.; Paquet, M.; Martel, C.; Bosschaerts, T.; Stienstra, S.; Olivier, M.; Fortin, A. Drug delivery by tattooing to treat cutaneous leishmaniasis. Sci. Rep., 2014, 4, 4156.
[http://dx.doi.org/10.1038/srep04156] [PMID: 24561704]
[37]
Barbosa, T.P.; Sousa, S.C.O.; Amorim, F.M.; Rodrigues, Y.K.S.; de Assis, P.A.C.; Caldas, J.P.A.; Oliveira, M.R.; Vasconcellos, M.L. Design, synthesis and antileishmanial in vitro activity of new series of chalcones-like compounds: a molecular hybridization approach. Bioorg. Med. Chem., 2011, 19(14), 4250-4256.
[http://dx.doi.org/10.1016/j.bmc.2011.05.055] [PMID: 21684751]
[38]
Rodrigues, K.A. da F.; Amorim, L.V.; Dias, C.N.; Moraes, D.F.C.; Carneiro, S.M.P.; Carvalho, F.A. Syzygium cumini (L.) Skeels essential oil and its major constituent α-pinene exhibit anti-Leishmania activity through immunomodulation in vitro. J. Ethnopharmacol., 2015, 160, 32-40.
[http://dx.doi.org/10.1016/j.jep.2014.11.024] [PMID: 25460590]
[39]
Aliança, A.S.D.S.; Oliveira, A.R.; Feitosa, A.P.S.; Ribeiro, K.R.C.; de Castro, M.C.A.B.; Leite, A.C.L.; Alves, L.C.; Brayner, F.A. In vitro evaluation of cytotoxicity and leishmanicidal activity of phthalimido-thiazole derivatives. Eur. J. Pharm. Sci., 2017, 105, 1-10.
[http://dx.doi.org/10.1016/j.ejps.2017.05.005] [PMID: 28478133]
[40]
Alexander, D.L.J.; Tropsha, A.; Winkler, D.A. Beware of R(2): simple, unambiguous assessment of the prediction accuracy of qsar and qspr models. J. Chem. Inf. Model., 2015, 55(7), 1316-1322.
[http://dx.doi.org/10.1021/acs.jcim.5b00206] [PMID: 26099013]
[41]
Todeschini, R.; Mauri, A.; Consonni, V.; Pavan, M. MobyDigs: software for regression and classification models by genetic algorithms. in:Nature-inspired methods in chemometrics: genetic algorithms and artificial neural networks; Elsevier: Amsterdam, 2003.
[http://dx.doi.org/10.1016/S0922-3487(03)23005-7]
[42]
Trott, O.; Olson, A.J. Software News and update autodock vina: improving the speed and accuracy of docking with a new scoring function, eficiente optimization, and multithreading. J. Comput. Chem., 2009, 31, 455-461.
[PMID: 19499576]
[43]
Cosconati, S.; Forli, S.; Perryman, A.L.; Harris, R.; Goodsell, D.S.; Olson, A.J. Virtual screening with autodock: theory and practice. Expert Opin. Drug Discov., 2010, 5(6), 597-607.
[http://dx.doi.org/10.1517/17460441.2010.484460] [PMID: 21532931]
[44]
Mendonça, F.J.B. Junior; Lima-Neto, R.G.; de Oliveira, T.B.; Lima, M.C.A.; Pitta, I.R.; Galdino, S.L.; da Cruz, R.M.D.; de Araújo, R.S.A.; Neves, R.P. Synthesis and evaluation of the antifungal activity of 2- (substituted-amino)-4,5-dialkyl-thiophene-3-carbonitrile derivatives. Lat. Am. J. Pharm., 2011, 30, 1492-1499.
[45]
Souza, B.C.C.; De Oliveira, T.B.; Aquino, T.M.; de Lima, M.C.A.; Pitta, I.R.; Galdino, S.L.; Lima, E.O.; Gonçalves-Silva, T.; Militão, G.C.; Scotti, L.; Scotti, M.T.; Mendonça, F.J.B. Jr Preliminary antifungal and cytotoxic evaluation of synthetic cycloalkyl[b]thiophene derivatives with PLS-DA analysis. Acta Pharm., 2012, 62(2), 221-236.
[http://dx.doi.org/10.2478/v10007-012-0017-y] [PMID: 22750820]
[46]
Huang, Y.; Dömling, A. The Gewald multicomponent reaction. Mol. Divers., 2011, 15(1), 3-33.
[http://dx.doi.org/10.1007/s11030-010-9229-6] [PMID: 20191319]

Rights & Permissions Print Cite
Article Metrics
13
© 2024 Bentham Science Publishers | Privacy Policy