Spiro-Lactams as Novel Antimicrobial Agents

Author(s): Américo J.S. Alves, Nuno G. Alves, Cátia C. Caratão, Margarida I.M. Esteves, Diana Fontinha, Inês Bártolo, Maria I.L. Soares, Susana M.M. Lopes, Miguel Prudêncio, Nuno Taveira, Teresa M.V.D. Pinho e Melo*

Journal Name: Current Topics in Medicinal Chemistry

Volume 20 , Issue 2 , 2020


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Abstract:

Introduction: Structural modulation of previously identified lead spiro-β-lactams with antimicrobial activity was carried out.

Objective: The main objective of this work was to synthesize and evaluate the biological activity of novel spiro-lactams based on previously identified lead compounds with antimicrobial activity.

Methods: The target chiral spiro-γ-lactams were synthesized through 1,3-dipolar cycloaddition reaction of a diazo-γ-lactam with electron-deficient dipolarophiles. In vitro activity against HIV and Plasmodium of a wide range of spiro-β-lactams and spiro-γ-lactams was evaluated. Among these compounds, one derivative with good anti-HIV activity and two with promising antiplasmodial activity (IC50 < 3.5 µM) were identified.

Results: A novel synthetic route to chiral spiro-γ-lactams has been established. The studied β- and γ- lactams were not cytotoxic, and three compounds with promising antimicrobial activity were identified, whose structural modulation may lead to new and more potent drugs.

Conclusion: The designed structural modulation of biologically active spiro-β-lactams involved the replacement of the four-membered β-lactam ring by a five-membered γ-lactam ring. Although conformational and superimposition computational studies revealed no significant differences between β- and γ- lactam pharmacophoric features, the studied structural modulation did not lead to compounds with a similar biological profile. The observed results suggest that the β-lactamic core is a requirement for the activity against both HIV and Plasmodium.

Keywords: Anti-HIV Agents, Antiplasmodial Agents, Spiro-γ-lactams, Spiro-penicillanate, 5-Oxohexahydropyrrolo[2, 1- b]thiazoles, Dipolar Cycloaddition, Diazo Compounds.

[1]
Arya, N.; Jagdale, A.Y.; Patil, T.A.; Yeramwar, S.S.; Holikatti, S.S.; Dwivedi, J.; Shishoo, C.J.; Jain, K.S. The chemistry and biological potential of azetidin-2-ones. Eur. J. Med. Chem., 2014, 74, 619-656.
[http://dx.doi.org/10.1016/j.ejmech.2014.01.002] [PMID: 24531200]
[2]
Mehta, P.D.; Sengar, N.P.S.; Pathak, A.K. 2-Azetidinone-a new profile of various pharmacological activities. Eur. J. Med. Chem., 2010, 45(12), 5541-5560.
[http://dx.doi.org/10.1016/j.ejmech.2010.09.035] [PMID: 20970895]
[3]
Galletti, P.; Giacomini, D. Monocyclic β-lactams: new structures for new biological activities. Curr. Med. Chem., 2011, 18(28), 4265-4283.
[http://dx.doi.org/10.2174/092986711797200480] [PMID: 21861821]
[4]
Hosseyni, S.; Jarrahpour, A. Recent advances in β-lactam synthesis. Org. Biomol. Chem., 2018, 16(38), 6840-6852.
[http://dx.doi.org/10.1039/C8OB01833B] [PMID: 30209477]
[5]
Decuyper, L.; Jukič, M.; Sosič, I.; Žula, A.; D’hooghe, M.; Gobec, S. Antibacterial and β-lactamase inhibitory activity of monocyclic β-lactams. Med. Res. Rev., 2018, 38(2), 426-503.
[http://dx.doi.org/10.1002/med.21443] [PMID: 28815732]
[6]
Singh, G.S.; D’hooghe, M.; De Kimpe, N. Synthesis and reactivity of spiro-fused β-lactams. Tetrahedron, 2011, 67(11), 1989-2012.
[http://dx.doi.org/10.1016/j.tet.2011.01.013]
[7]
Vandekerckhove, S.; D’hooghe, M. Exploration of aziridine- and β-lactam-based hybrids as both bioactive substances and synthetic intermediates in medicinal chemistry. Bioorg. Med. Chem., 2013, 21(13), 3643-3647.
[http://dx.doi.org/10.1016/j.bmc.2013.04.033] [PMID: 23684232]
[8]
Majewski, M.W.; Miller, P.A.; Oliver, A.G.; Miller, M.J. Alternate “drug” delivery utilizing b-lactam cores: Syntheses and biological evaluation of b-lactams bearing isocyanate precursors. J. Org. Chem., 2017, 82(1), 737-744.
[http://dx.doi.org/10.1021/acs.joc.6b02272] [PMID: 27935702]
[9]
Alborz, M.; Jarrahpour, A.; Pournejati, R.; Karbalaei-Heidari, H.R.; Sinou, V.; Latour, C.; Brunel, J.M.; Sharghi, H.; Aberi, M.; Turos, E.; Wojtas, L. Synthesis and biological evaluation of some novel diastereoselective benzothiazole β-lactam conjugates. Eur. J. Med. Chem., 2018, 143, 283-291.
[http://dx.doi.org/10.1016/j.ejmech.2017.11.053] [PMID: 29197733]
[10]
Giacomini, D.; Martelli, G.; Piccichè, M.; Calaresu, E.; Cocuzza, C.E.; Musumeci, R. Design and synthesis of 4-alkylidene-β-lactams: Benzyl- and phenethyl-carbamates as key fragments to switch on antibacterial activity. ChemMedChem, 2017, 12(18), 1525-1533.
[http://dx.doi.org/10.1002/cmdc.201700307] [PMID: 28737008]
[11]
Jarrahpour, A.; Ebrahimi, E.; De Clercq, E.; Sinou, V.; Latour, C.; Bouktab, L.D.; Brunel, J.M. Synthesis of mono-, bis-spiro- and dispiro-β-lactams and evaluation of their antimalarial activities. Tetrahedron, 2011, 67(45), 8699-8704.
[http://dx.doi.org/10.1016/j.tet.2011.09.041]
[12]
Raj, R.; Biot, C.; Carrère-Kremer, S.; Kremer, L.; Guérardel, Y.; Gut, J.; Rosenthal, P.J.; Kumar, V. 4-Aminoquinoline-β-lactam conjugates: synthesis, antimalarial, and antitubercular evaluation. Chem. Biol. Drug Des., 2014, 83(2), 191-197.
[http://dx.doi.org/10.1111/cbdd.12225] [PMID: 24034147]
[13]
Dražić, T.; Sachdev, V.; Leopold, C.; Patankar, J.V.; Malnar, M.; Hećimović, S.; Levak-Frank, S.; Habuš, I.; Kratky, D. Synthesis and evaluation of novel amide amino-β-lactam derivatives as cholesterol absorption inhibitors. Bioorg. Med. Chem., 2015, 23(10), 2353-2359.
[http://dx.doi.org/10.1016/j.bmc.2015.03.067] [PMID: 25882530]
[14]
Baiula, M.; Galletti, P.; Martelli, G.; Soldati, R.; Belvisi, L.; Civera, M.; Dattoli, S.D.; Spampinato, S.M.; Giacomini, D. New β-lactam derivatives modulate cell adhesion and signaling mediated by RGD-binding and leukocyte integrins. J. Med. Chem., 2016, 59(21), 9721-9742.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00576] [PMID: 27726366]
[15]
Zhou, P.; Liu, Y.; Zhou, L.; Zhu, K.; Feng, K.; Zhang, H.; Liang, Y.; Jiang, H.; Luo, C.; Liu, M.; Wang, Y. Potent antitumor activities and structure basis of the chiral β-lactam bridged analogue of combretastatin A-4 binding to tubulin. J. Med. Chem., 2016, 59(22), 10329-10334.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01268] [PMID: 27805821]
[16]
Barrett, A.G.M.; Head, J.; Smith, M.L.; Stock, N.S.; White, A.J.P.; Williams, D.J. Fleming-Tamao oxidation and masked hydroxyl functionality: Total synthesis of (+)-pramanicin and structural elucidation of the antifungal natural product (-)-pramanicin. J. Org. Chem., 1999, 64(16), 6005-6018.
[http://dx.doi.org/10.1021/jo9905672]
[17]
Baures, P.W.; Eggleston, D.S.; Erhard, K.F.; Cieslinski, L.B.; Torphy, T.J.; Christensen, S.B. The crystal structure, absolute configuration, and phosphodiesterase inhibitory activity of (+)-1-(4-bromobenzyl)-4-(3-(cyclopentyloxy)- 4-methoxyphenyl)-pyrrolidin-2-one. J. Med. Chem., 1993, 36(22), 3274-3277.
[http://dx.doi.org/10.1021/jm00074a007] [PMID: 8230117]
[18]
Davies, M.N.; Bayry, J.; Tchilian, E.Z.; Vani, J.; Shaila, M.S.; Forbes, E.K.; Draper, S.J.; Beverley, P.C.L.; Tough, D.F.; Flower, D.R. Toward the discovery of vaccine adjuvants: coupling in silico screening and in vitro analysis of antagonist binding to human and mouse CCR4 receptors. PLoS One, 2009, 4(11) e8084
[http://dx.doi.org/10.1371/journal.pone.0008084] [PMID: 20011659]
[19]
Feling, R.H.; Buchanan, G.O.; Mincer, T.J.; Kauffman, C.A.; Jensen, P.R.; Fenical, W.; Salinosporamide, A. Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora. Angew. Chem. Int. Ed. Engl., 2003, 42(3), 355-357.
[http://dx.doi.org/10.1002/anie.200390115] [PMID: 12548698]
[20]
Newhouse, B.; Allen, S.; Fauber, B.; Anderson, A.S.; Eary, C.T.; Hansen, J.D.; Schiro, J.; Gaudino, J.J.; Laird, E.; Chantry, D.; Eberhardt, C.; Burgess, L.E. Racemic and chiral lactams as potent, selective and functionally active CCR4 antagonists. Bioorg. Med. Chem. Lett., 2004, 14(22), 5537-5542.
[http://dx.doi.org/10.1016/j.bmcl.2004.09.001] [PMID: 15482919]
[21]
Pyun, D.K.; Kim, B.J.; Jung, H.J.; Kim, J.H.; Lee, J.S.; Lee, W.K.; Lee, C.H. Syntheses of 1β-methylcarbapenems bearing 5-methyl-4-hydroxypyrrolidinone. Chem. Pharm. Bull. (Tokyo), 2002, 50(3), 415-418.
[http://dx.doi.org/10.1248/cpb.50.415] [PMID: 11911211]
[22]
Santos, B.S.; Nunes, S.C.C.; Pais, A.A.C.C.; Pinho e Melo, T.M.V.D. Chiral spiro-β-lactams from 6-diazopenicillanates. Tetrahedron, 2012, 68(19), 3729-3737.
[http://dx.doi.org/10.1016/j.tet.2012.03.022]
[23]
Santos, B.S.; Gomes, C.S.B.; Pinho e Melo, T.M.V.D. Synthesis of chiral spiropyrazoline-beta-lactams and spirocyclopropyl-β-lactams from 6-alkylidenepenicillanates. Tetrahedron, 2014, 70(24), 3812-3821.
[http://dx.doi.org/10.1016/j.tet.2014.03.109]
[24]
Santos, B.S.; Pinho e Melo, T.M.V.D. Synthesis of chiral spirocyclopentenyl-β-lactams through phosphane-catalyzed [3+2] annulation of allenoates with 6-alkylidenepenicillanates. Eur. J. Org. Chem., 2013, (18), 3901-3909.
[http://dx.doi.org/10.1002/ejoc.201300153]
[25]
Pinho e Melo, T. M. V. D.; Taveira, N.; Prudêncio, M.; Santos, B. S.; Bártolo, I. Novel spiro-lactams, process and uses thereof. WO/2018/207165 2017.
[26]
Blanca-Lopez, N.; Jimenez-Rodriguez, T.W.; Somoza, M.L.; Gomez, E.; Al-Ahmad, M.; Perez-Sala, D.; Blanca, M. Allergic reactions to penicillins and cephalosporins: diagnosis, assessment of cross-reactivity and management. Expert Rev. Clin. Immunol., 2019, 15(7), 707-721.
[http://dx.doi.org/10.1080/1744666X.2019.1619548] [PMID: 31161822]
[27]
FDA. Non-Penicillin Beta-Lactam Drugs: A CGMP framework for preventing cross-contamination.. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/non-penicillin-beta-lactam-drugs-cgmp-framework-preventing-cross-contamination (accessed August 27, 2019).
[28]
Brasile, G.; Mauri, L.; Sonnino, S.; Compostella, F.; Ronchetti, F. A practical route to long-chain non-natural α,ω-diamino acids. Amino Acids, 2013, 44(2), 435-441.
[http://dx.doi.org/10.1007/s00726-012-1349-0] [PMID: 22777284]
[29]
Martín-Martínez, M.; De La Figuera, N.; Latorre, M.; Herranz, R.; García-López, M.T.; Cenarruzabeitia, E.; Del Río, J.; González-Muñiz, R. β-Turned dipeptoids as potent and selective CCK(1) receptor antagonists. J. Med. Chem., 2000, 43(20), 3770-3777.
[http://dx.doi.org/10.1021/jm000959x] [PMID: 11020292]
[30]
Borrego, P.; Calado, R.; Marcelino, J.M.; Bártolo, I.; Rocha, C.; Cavaco-Silva, P.; Doroana, M.; Antunes, F.; Maltez, F.; Caixas, U.; Barroso, H.; Taveira, N. Baseline susceptibility of primary HIV-2 to entry inhibitors. Antivir. Ther. (Lond.), 2012, 17(3), 565-570.
[http://dx.doi.org/10.3851/IMP1996] [PMID: 22293827]
[31]
Davis, K.L.; Bibollet-Ruche, F.; Li, H.; Decker, J.M.; Kutsch, O.; Morris, L.; Salomon, A.; Pinter, A.; Hoxie, J.A.; Hahn, B.H.; Kwong, P.D.; Shaw, G.M. Human immunodeficiency virus type 2 (HIV-2)/HIV-1 envelope chimeras detect high titers of broadly reactive HIV-1 V3-specific antibodies in human plasma. J. Virol., 2009, 83(3), 1240-1259.
[http://dx.doi.org/10.1128/JVI.01743-08] [PMID: 19019969]
[32]
Borrego, P.; Calado, R.; Marcelino, J.M.; Pereira, P.; Quintas, A.; Barroso, H.; Taveira, N. An ancestral HIV-2/simian immunodeficiency virus peptide with potent HIV-1 and HIV-2 fusion inhibitor activity. AIDS, 2013, 27(7), 1081-1090.
[http://dx.doi.org/10.1097/QAD.0b013e32835edc1d] [PMID: 23324659]
[33]
Ploemen, I.H.J.; Prudêncio, M.; Douradinha, B.G.; Ramesar, J.; Fonager, J.; van Gemert, G-J.; Luty, A.J.F.; Hermsen, C.C.; Sauerwein, R.W.; Baptista, F.G.; Mota, M.M.; Waters, A.P.; Que, I.; Lowik, C.W.G.M.; Khan, S.M.; Janse, C.J.; Franke-Fayard, B.M.D. Visualisation and quantitative analysis of the rodent malaria liver stage by real time imaging. PLoS One, 2009, 4(11) e7881
[http://dx.doi.org/10.1371/journal.pone.0007881] [PMID: 19924309]
[34]
Prudêncio, M.; Rodrigues, C.D.; Ataíde, R.; Mota, M.M. Dissecting in vitro host cell infection by Plasmodium sporozoites using flow cytometry. Cell. Microbiol., 2008, 10(1), 218-224.
[PMID: 17697130]
[35]
Becke, A.D. Density-functional exchange-energy approximation with correct asymptotic behavior. Phys. Rev. A Gen. Phys., 1988, 38(6), 3098-3100.
[http://dx.doi.org/10.1103/PhysRevA.38.3098] [PMID: 9900728]
[36]
Becke, A.D. Density-functional thermochemistry. The role of exact exchange. J. Chem. Phys., 1993, 98(7), 5648-5652.
[http://dx.doi.org/10.1063/1.464913]
[37]
Lee, C.; Yang, W.; Parr, R.G. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B Condens. Matter, 1988, 37(2), 785-789.
[http://dx.doi.org/10.1103/PhysRevB.37.785] [PMID: 9944570]
[38]
Schmidt, M.W.; Baldridge, K.K.; Boatz, J.A.; Elbert, S.T.; Gordon, M.S.; Jensen, J.H.; Koseki, S.; Matsunaga, N.; Nguyen, K.A.; Su, S.J.; Windus, T.L.; Dupuis, M.; Montgomery, J.A. General atomic and molecular electronic structure system. J. Comput. Chem., 1993, 14(11), 1347-1363.
[http://dx.doi.org/10.1002/jcc.540141112]
[39]
Wolber, G.; Langer, T. LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J. Chem. Inf. Model., 2005, 45(1), 160-169.
[http://dx.doi.org/10.1021/ci049885e] [PMID: 15667141]
[40]
Baldwin, J.E.; Freeman, R.T.; Lowe, C.; Schofield, C.J.; Lee, E. A γ-lactam analog of the penems possessing antibacterial activity. Tetrahedron, 1989, 45(14), 4537-4550.
[http://dx.doi.org/10.1016/S0040-4020(01)89088-8]
[41]
Baldwin, J.E.; Lowe, C.; Schofield, C.J.; Lee, E. A γ-lactam analog of the penems possessing antibacterial activity. Tetrahedron Lett., 1986, 27(30), 3461-3464.
[http://dx.doi.org/10.1016/S0040-4039(00)84822-4]
[42]
Chauvette, R.R.; Pennington, P.A.; Ryan, C.W.; Cooper, R.D.G.; José, F.L.; Wright, I.G.; Van Heyningen, E.M.; Huffman, G.W. Chemistry of cephalosporin antibiotics. XXI. Conversion of penicillins to cephalexin. J. Org. Chem., 1971, 36(9), 1259-1267.
[http://dx.doi.org/10.1021/jo00808a021] [PMID: 4995070]
[43]
Sheehan, J.C.; Commons, T.J. Reaction of 6(7)-diazopenicillanates and diazocephalosporanates with sulfenyl chlorides. Preparation of 6(7)α-methoxy-substituted thiol penicillanates and thiol cephalosporanates. J. Org. Chem., 1978, 43(11), 2203-2208.
[http://dx.doi.org/10.1021/jo00405a026]


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VOLUME: 20
ISSUE: 2
Year: 2020
Published on: 19 February, 2020
Page: [140 - 152]
Pages: 13
DOI: 10.2174/1568026619666191105110049
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