Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Synthesis, Docking Studies, and Biological Evaluation of Betti Bases as Promising Anti-tubercular Agents

Author(s): Poornima Acharya, Mucheli Muni Venkata Ramana*, Nilesh Korgavkar, Ganesh Pavale and Manish Upadhyay

Volume 20, Issue 6, 2023

Published on: 03 September, 2022

Page: [724 - 737] Pages: 14

DOI: 10.2174/1570180819666220520141039

Price: $65

Abstract

Background: The occurrence of Tuberculosis (TB) has significantly increased worldwide. The extensively drug-resistant tuberculosis (XDR-TB) and multi-drug resistant tuberculosis (MDR-TB) have made it more challenging to treat this mycobacterial infection caused by the Mycobacterium tuberculosis MTB-H37Rv strain. The present treatments for tuberculosis are of long duration and with side effects. Thus, it is necessary to discover new drugs with short-term chemotherapy, fewer health hazards, and cost effectiveness.

Objective: The objective of the study was to divulge the antitubercular properties of Betti base scaffolds.

Method: Betti bases were designed, synthesized 4a-4h, 6a-6h, and investigated for their in vitro antitubercular activity using Microplate Alamar Blue assay (MABA) against the MTB-H37Rv strain. Their binding affinity with amino acids was studied by performing molecular docking studies using InhA (PDB ID: 2NSD) present in the MTB-H37Rv strain. Cytotoxicity assay and neutrophil function test (NFT) were also performed.

Results: The Betti bases (4a-4h, 6d) showed minimum inhibitory concentration (MIC) values ranging from 1.6 μg/mL to 6.25 μg/mL against the MTB-H37Rv strain. The compounds (4a-4h, 6a-6h) were investigated for their ADME properties and good pharmacokinetic profiles were observed. In molecular docking studies, a strong binding affinity between InhA and the compounds (4a-4h, 6a-6h) was observed, which provided theoretical insight into the inhibitory action of the synthesized compounds (4a-4h, 6a-6h) against InhA. NFT of the compounds (4a-4h, 6a-6h) showed no harmful effects on the functions of neutrophils. In vitro cytotoxicity assay against Vero cell lines revealed the non-cytotoxic behavior of the compounds.

Conclusion: Betti bases can be considered to be a promising class of molecular entities that can lead to the development of new anti-tubercular leads.

Keywords: Betti bases, docking studies with InhA, microplate alamar blue assay (MABA), neutrophil function test (NFT), in vitro cytotoxicity assay, drug resistant.

Graphical Abstract

[1]
Šlachtová, V.; Brulíková, L. Benzoxazole derivatives as promising antitubercular agents. Chem. Sel., 2018, 3(17), 4653-4662.
[http://dx.doi.org/10.1002/slct.201800631]
[2]
Chin, K.L.; Sarmiento, M.E.; Alvarez-Cabrera, N.; Norazmi, M.N.; Acosta, A. Pulmonary non-tuberculous mycobacterial infections: current state and future management. Eur. J. Clin. Microbiol. Infect. Dis., 2020, 39(5), 799-826.
[http://dx.doi.org/10.1007/s10096-019-03771-0] [PMID: 31853742]
[3]
Barry, C.E., III; Blanchard, J.S. The chemical biology of new drugs in the development for tuberculosis. Curr. Opin. Chem. Biol., 2010, 14(4), 456-466.
[http://dx.doi.org/10.1016/j.cbpa.2010.04.008] [PMID: 20452813]
[4]
WHO. Global tuberculosis report., 2018. Available from: https://www.who.int/teams/global-tuberculosis-programme/tb-reports
[5]
[6]
Reddyrajula, R.; Dalimba, U. Quinoline-1,2,3-triazole hybrids: Design and synthesis through click reaction, evaluation of anti-tubercular activity, molecular docking and in silico ADME studies. Chem. Sel., 2019, 4(9), 2685-2693.
[http://dx.doi.org/10.1002/slct.201803946]
[7]
Baravkar, S.B.; Wagh, M.A.; Nawale, L.U.; Choudhari, A.S.; Bhansali, S.; Sarkar, D.; Sanjayan, G.J. Design and synthesis of 2-amino-thiophene-proline-conjugates and their anti-tubercular activity against mycobacterium tuberculosis H37Ra. Chem. Sel., 2019, 4(9), 2851-2857.
[http://dx.doi.org/10.1002/slct.201803370]
[8]
Nayak, N.; Ramprasad, J.; Dalimba, U.; Yogeeswari, P.; Sriram, D.; Kumar, H.S.S.; Peethambar, S.K.; Achur, R. Synthesis of new pyrazole-triazole hybrids by click reaction using a green solvent and evaluation of their antitubercular and antibacterial activity. Res. Chem. Intermed., 2016, 42(4), 3721-3741.
[http://dx.doi.org/10.1007/s11164-015-2241-9]
[9]
Reddyrajula, R.; Dalimba, U. The bioisosteric modification of pyrazinamide derivatives led to potent antitubercular agents: Synthesis via click approach and molecular docking of pyrazine-1,2,3-triazoles. Bioorg. Med. Chem. Lett., 2020, 30(2), 126846.
[http://dx.doi.org/10.1016/j.bmcl.2019.126846] [PMID: 31839540]
[10]
Šink, R.; Sosiič, I.; Živec, M.; Fernandez-Menendez, R.; Turk, S.; Pajk, S.; Alvarez-Gomez, D.; Lopez-Roman, E.M.; Gonzales-Cortez, C.; Rullas-Triconado, J.; Angulo-Barturen, I.; Barros, D.; Ballell-Pages, L.; Young, R.J.; Encinas, L.; Gobec, S. Design, synthesis, and evaluation of new thiadiazole-based direct inhibitors of enoyl acyl carrier protein reductase (InhA) for the treatment of tuberculosis. J. Med. Chem., 2015, 58(2), 613-624.
[http://dx.doi.org/10.1021/jm501029r] [PMID: 25517015]
[11]
Kamsri, P.; Hanwarinroj, C.; Phusi, N.; Pornprom, T.; Chayajarus, K.; Punkvang, A.; Suttipanta, N.; Srimanote, P.; Suttisintong, K.; Songsiriritthigul, C.; Saparpakorn, P.; Hannongbua, S.; Rattanabunyong, S.; Seetaha, S.; Choowongkomon, K.; Sureram, S.; Kittakoop, P.; Hongmanee, P.; Santanirand, P.; Chen, Z.; Zhu, W.; Blood, R.A.; Takebayashi, Y.; Hinchliffe, P.; Mulholland, A.J.; Spencer, J.; Pungpo, P. Discovery of new and potent InhA inhibitors as antituberculosis agents: structure-based virtual screening validated by biological assays and X-ray crystallography. J. Chem. Inf. Model., 2020, 60(1), 226-234.
[http://dx.doi.org/10.1021/acs.jcim.9b00918] [PMID: 31820972]
[12]
Sullivan, T.J.; Truglio, J.J.; Boyne, M.E.; Novichenok, P.; Zhang, X.; Stratton, C.F.; Li, H-J.; Kaur, T.; Amin, A.; Johnson, F.; Slayden, R.A.; Kisker, C.; Tonge, P.J. High affinity InhA inhibitors with activity against drug-resistant strains of Mycobacterium tuberculosis. ACS Chem. Biol., 2006, 1(1), 43-53.
[http://dx.doi.org/10.1021/cb0500042] [PMID: 17163639]
[13]
He, X.; Alian, A.; Ortiz de Montellano, P.R. Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides. Bioorg. Med. Chem., 2007, 15(21), 6649-6658.
[http://dx.doi.org/10.1016/j.bmc.2007.08.013] [PMID: 17723305]
[14]
Chollet, A.; Maveyraud, L.; Lherbet, C.; Bernardes-Génisson, V. An overview on crystal structures of InhA protein: Apo-form, in complex with its natural ligands and inhibitors. Eur. J. Med. Chem., 2018, 146, 318-343.
[15]
Rivers, E.C.; Mancera, R.L. New anti-tuberculosis drugs in clinical trials with novel mechanisms of action. Drug Discov. Today, 2008, 13(23-24), 1090-1098.
[http://dx.doi.org/10.1016/j.drudis.2008.09.004] [PMID: 18840542]
[16]
Caminero, J.A.; Scardigli, A. Classification of antituberculosis drugs: A new proposal based on the most recent evidence. Eur. Respir. J., 2015, 46(4), 887-893.
[http://dx.doi.org/10.1183/13993003.00432-2015]
[17]
Khade, A.B.; Eshwara, V.K.; Boshoff, H.I.M.; Arora, K.; Tiwari, A.; Bhat, P.; Tiwari, M.; Shenoy, G.G. Design, synthesis, biological evaluation and molecular dynamic simulation studies of diphenyl ether derivatives as antitubercular and antibacterial agents. ChemistrySelect, 2020, 5(1), 201-210.
[http://dx.doi.org/10.1002/slct.201903305]
[18]
Guo, S.; Song, Y.; Huang, Q.; Yuan, H.; Wan, B.; Wang, Y.; He, R.; Beconi, M.G.; Franzblau, S.G.; Kozikowski, A.P. Identification, synthesis, and pharmacological evaluation of tetrahydroindazole based ligands as novel antituberculosis agents. J. Med. Chem., 2010, 53(2), 649-659.
[http://dx.doi.org/10.1021/jm901235p] [PMID: 20000470]
[19]
Shaikh, F.; Shastri, S.L.; Naik, N.S.; Kulkarni, R.; Madar, J.M.; Shastri, L.A.; Joshi, S.D.; Sunagar, V. Synthesis, antitubercular and antimicrobial activity of 1,2,4-triazolidine-3-thione functionalized coumarin and phenyl derivatives and molecular docking studies. Chem. Sel., 2019, 4(1), 105-115.
[http://dx.doi.org/10.1002/slct.201802395]
[20]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2012, 64(Suppl.), 4-17.
[http://dx.doi.org/10.1016/j.addr.2012.09.019] [PMID: 11259830]
[21]
Mohanram, I.; Meshram, J. Synthesis and biological activities of 4-aminoantipyrine derivatives derived from betti-type reaction. ISRN Org. Chem., 2014, 2014, 639392.
[http://dx.doi.org/10.1155/2014/639392] [PMID: 24955256]
[22]
Olyaei, A.; Sadeghpour, M. Recent advances in the synthesis and synthetic applications of betti base (aminoalkylnaphthol) and bis-betti base derivatives. RSC Advances, 2019, 9(32), 18467-18497.
[http://dx.doi.org/10.1039/C9RA02813G]
[23]
Pegu, C.D.; Nasrin, S.B.; Deb, M.L.; Das, D.J.; Saikia, K.K.; Baruah, P.K. CAN-Catalyzed microwave promoted reaction of indole with betti bases under solvent-free condition and evaluation of antibacterial activity of the products. Synth. Commun., 2017, 47(21), 2007-2014.
[http://dx.doi.org/10.1080/00397911.2017.1360912]
[24]
Sahu, P.K.; Sahu, P.K.; Thavaselvam, D.; Alafeefy, A.M.; Agarwal, D.D. Synthesis and evaluation of antimicrobial activity of 2-aminobenzothiazolomethyl naphthol derivatives. Med. Chem. Res., 2015, 24, 725-736.
[http://dx.doi.org/10.1007/s00044-014-1150-6]
[25]
Anary-abbasinejad, M.; Hassanabadi, A.; Kamali-gharamaleki, M.; Saidipoor, A.; Anaraki-ardakani, H. Three-component reaction between 2-naphthol, aromatic aldehydes and acetonitrile in the presence of chlorosulfonic acid yields 1- (acetylamino (aryl) methyl) -2-naphthols. J. Chem. Res., 2007, 11, 644-646.
[http://dx.doi.org/10.3184/030823407X266207]
[26]
Gadilohar, B.L.; Kumbhar, H.S.; Shankarling, G.S. Choline peroxydisulfate oxidizing Bio-TSIL: Triple role player in the one-pot synthesis of betti bases and gem-bisamides from aryl alcohols under solvent-free conditions. New J. Chem., 2015, 39, 4647-4657.
[http://dx.doi.org/10.1039/C4NJ02295E]
[27]
Nandi, G.C.; Samai, S.; Kumar, R.; Singh, M.S. Atom-efficient and environment-friendly multicomponent synthesis of amidoalkyl naphthols catalyzed by P2O5. Tetrahedron Lett., 2009, 50(51), 7220-7222.
[http://dx.doi.org/10.1016/j.tetlet.2009.10.055]
[28]
Karmakar, B.; Banerji, J. A competent pot and atom-efficient synthesis of betti bases over nanocrystalline MgO involving a modified mannich type reaction. Tetrahedron Lett., 2011, 52(38), 4957-4960.
[http://dx.doi.org/10.1016/j.tetlet.2011.07.075]
[29]
Kiyani, H.; Darbandi, H.; Mosallanezhad, A.; Ghorbani, F. 2-hydroxy-5-sulfobenzoic acid: An efficient organocatalyst for the three-component synthesis of 1-amidoalkyl-2-naphthols and 3,4-disubstituted isoxazol-5(4H)-ones. Res. Chem. Intermed., 2015, 41(10), 7561-7579.
[http://dx.doi.org/10.1007/s11164-014-1844-x]
[30]
Kumar, A.; Gupta, M.K.; Kumar, M. Non-ionic surfactant catalyzed synthesis of betti base in water. Tetrahedron Lett., 2010, 51(12), 1582-1584.
[http://dx.doi.org/10.1016/j.tetlet.2010.01.056]
[31]
Su, W.; Tang, W.; Li, J. Strontium(II) triflate catalysed condensation of β-naphthol, aldehyde and urea or amides: A facile synthesis of amidoalkyl naphthols. J. Chem. Res., 2008, (3), 123-128.
[http://dx.doi.org/10.3184/030823408X298508]
[32]
Cai, X.; Xie, B. One-pot multi-component synthesis of amidoalkyl naphthols with potassium hydrogen sulfate as catalyst under solvent-free condition. Int. J. Chem., 2011, 3(1), 119-122.
[33]
Shaterian, H.R.; Yarahmadi, H.; Ghashang, M. Silica supported perchloric acid (HClO4-SiO2): An efficient and recyclable heterogeneous catalyst for the one-pot synthesis of amidoalkyl naphthols. Tetrahedron, 2008, 64(7), 1263-1269.
[http://dx.doi.org/10.1016/j.tet.2007.11.070]
[34]
Safari, J.; Zarnegar, Z. A magnetic nanoparticle-supported sulfuric acid as a highly efficient and reusable catalyst for rapid synthesis of amidoalkyl naphthols. J. Mol. Catal. Chem., 2016, 2013(379), 269-276.
[http://dx.doi.org/10.1016/j.molcata.2013.08.028]
[35]
Kantevari, S.; Vuppalapati, S.V.N.; Nagarapu, L. Montmorillonite K10 catalyzed efficient synthesis of amidoalkyl naphthols under solvent free conditions. Catal. Commun., 2007, 8(11), 1857-1862.
[http://dx.doi.org/10.1016/j.catcom.2007.02.022]
[36]
Janati, F.; Heravi, M.M.; Shokraie, A.M. Solventless synthesis of 1-(α-aminoalkyl) naphthols, betti bases, catalyzed by nanoparticle Fe3O4 at room temperature. Synth. React. Inorg. Met. Nano-Metal Chem., 2015, 45(1), 1-5.
[http://dx.doi.org/10.1080/15533174.2012.762381]
[37]
Khodaei, M.; Khosropour, A.R. A simple and efficient procedure for the synthesis of amidoalkyl naphthols by p -TSA in solution or under solvent-free conditions. Synlett, 2006, 6, 916-920.
[http://dx.doi.org/10.1055/s-2006-939034]
[38]
Nagarapu, L.; Baseeruddin, M.; Apuri, S.; Kantevari, S. Potassium dodecatungstocobaltate trihydrate (K5CoW12O40 · 3H2O): A mild and efficient reusable catalyst for the synthesis of amidoalkyl naphthols in solution and under solvent-free conditions. Catal. Commun., 2007, 8(11), 1729-1734.
[http://dx.doi.org/10.1016/j.catcom.2007.02.008]
[39]
Shaikh, K.A.; Chaudhar, U.N.; Ningdale, V.B. Citric acid catalyzed synthesis of amidoalkyl naphthols under solvent-free condition_ :An eco-friendly protocol. J. Appl. Chem., 2014, 7(4), 90-93.
[http://dx.doi.org/10.9790/5736-07429093]
[40]
Srihari, G.; Nagaraju, M.; Murthy, M.M. Solvent-free one-pot synthesis of amidoalkyl naphthols catalyzed by silica sulfuric acid. Helv. Chim. Acta, 2007, 90(8), 1497-1504.
[http://dx.doi.org/10.1002/hlca.200790156]
[41]
Collins, L.; Franzblau, S.G. Microplate alamar blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrob. Agents Chemother., 1997, 41(5), 1004-1009.
[http://dx.doi.org/10.1128/AAC.41.5.1004] [PMID: 9145860]
[42]
Cho, S.; Lee, H.S.; Franzblau, S. Microplate alamar blue assay (MABA) and low oxygen recovery assay (LORA) for Mycobacterium tuberculosis. Methods Mol. Biol., 2015, 1285, 281-292.
[http://dx.doi.org/10.1007/978-1-4939-2450-9_17] [PMID: 25779323]
[43]
Cinu, T.A.; Sidhartha, S.K.; Indira, B.; Varadaraj, B.G.; Vishnu, P.S.; Shenoy, G.G. Design, synthesis and evaluation of antitubercular activity of triclosan analogues. Arab. J. Chem., 2019, 12(8), 3316-3323.
[44]
Joseph, J.; Dixit, S.R.; Pujar, G.V. Design, synthesis and in vitro evaluation of aryl amides as potent inhibitors against Mycobacterium tuberculosis. J. Pharm. Sci. Res., 2019, 11(9), 3166-3173.
[45]
Senthilraja, P.; Kathiresan, K. In vitro cytotoxicity MTT assay in vero, hepg2 and mcf-7 cell lines study of marine yeast. J. Appl. Pharm. Sci., 2015, 5(3), 80-84.
[http://dx.doi.org/10.7324/JAPS.2015.50313]
[46]
Patel, S.; Gheewala, N.; Suthar, A.; Shah, A. In-vitro cytotoxicity activity of solanum nigrum extract against hela cell line and vero cell line. Int. J. Pharm. Pharm. Sci., 2009, 1(Suppl. 1), 38-46.
[47]
Castelino, P.A.; Dasappa, J.P.; Bhat, K.G.; Joshi, S.A.; Jalalpure, S. Some novel schiff bases of [1,2,4]triazole bearing haloarene moiety - synthesis and evaluation of antituberculosis properties and neutrophil function test. Med. Chem. Res., 2016, 25(1), 83-93.
[http://dx.doi.org/10.1007/s00044-015-1461-2]
[48]
Matzner, Y. Neutrophil function studies in clinical medicine. Transfus. Med. Rev., 1987, 1(3), 171-181.
[http://dx.doi.org/10.1016/S0887-7963(87)70019-4] [PMID: 2980276]
[49]
Isyaku, Y.; Uzairu, A.; Uba, S. Heliyon computational studies of a series of 2-substituted phenyl-2-oxo-, 2-hydrox- yl- and 2-acylloxyethylsulfonamides as potent anti-fungal agents. Heliyon, 2020, 6e03724
[50]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2016, 2017(7), 1-13.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[51]
Lohidashan, K.; Rajan, M.; Ganesh, A.; Paul, M.; Jerin, J. Pass and Swiss ADME collaborated in silico docking approach to the synthesis of certain pyrazoline spacer compounds for dihydrofolate reductase inhibition and antimalarial activity. Bangladesh J. Pharmacol., 2018, 13(1), 23-29.
[http://dx.doi.org/10.3329/bjp.v13i1.33625]
[52]
Reddyrajula, R.; Dalimba, U.; Madan Kumar, S. Molecular hybridization approach for phenothiazine incorporated 1,2,3-triazole hybrids as promising antimicrobial agents: Design, synthesis, molecular docking and in silico ADME studies. Eur. J. Med. Chem., 2019, 168, 263-282.
[53]
Medić-Šarić, M.; Mornar, A.; Badovinac-Črnjević, T.; Jasprica, I. Experimental and calculation procedures for molecular lipophilicity: A comparative study for 3,3′-(2-methoxy benzylidene)bis(4-Hydroxycoumarin). Croat. Chem. Acta, 2004, 77(1-2), 367-370.
[54]
Cardellicchio, C.; Capozzi, M.A.M.; Naso, F. The betti base: The awakening of a sleeping beauty. Tetrahedron Asymmetry, 2010, 21(5), 507-517.
[http://dx.doi.org/10.1016/j.tetasy.2010.03.020]
[55]
Subramaniapillai, S.G.; Rajendran, N.; Sundarakumar, S.I.; Ganesan, A.; Pemiah, B. β-Naphthol in glycerol: A versatile pair for efficient and convenient synthesis of aminonaphthols, naphtho-1,3-oxazines, and benzoxanthenes. Synthesis (Stuttg), 2013, 45(11), 1564-1568.
[http://dx.doi.org/10.1055/s-0033-1338430]
[56]
Pulipati, L.; Yogeeswari, P.; Sriram, D.; Kantevari, S. Click-based synthesis and antitubercular evaluation of novel dibenzo [ b, d] Thiophene- 1, 2, 3-Triazoles with piperidine, piperazine, morpholine and thiomorpholine appendages. Bioorg. Med. Chem. Lett., 2016, 26(11), 2649.
[57]
Vitaku, E.; Smith, D.T.; Njardarson, J.T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem., 2014, 57(24), 10257-10274.
[http://dx.doi.org/10.1021/jm501100b] [PMID: 25255204]
[58]
Correa, R.M.D.S.; Mota, T.C.; Guimarães, A.C.; Bonfim, L.T.; Burbano, R.R.; Bahia, M.O. Cytotoxic and genotoxic effects of fluconazole on african green monkey kidney (vero) cell line. BioMed Res. Int., 2018, 2018, 6271547.
[http://dx.doi.org/10.1155/2018/6271547] [PMID: 30515410]
[59]
Ryder, M.I. Comparison of neutrophil functions in aggressive and chronic periodontitis. Periodontol. 2000, 2010, 53(53), 124-137.
[http://dx.doi.org/10.1111/j.1600-0757.2009.00327.x] [PMID: 20403109]
[60]
Nathan, C. Neutrophils and immunity: Challenges and opportunities. Nat. Rev. Immunol., 2006, 6(3), 173-182.
[http://dx.doi.org/10.1038/nri1785] [PMID: 16498448]
[61]
Dale, D.C.; Boxer, L.; Liles, W.C.; Ramaiah, M.; Vaidya, V.P.; Shivakumar, B.S. The phagocytes: Neutrophils and monocytes. Blood, 2008, 112(4), 935-945.
[http://dx.doi.org/10.1182/blood-2007-12-077917] [PMID: 18684880]
[62]
Moulkrere, B.R.; Orena, B.S.; Mori, G.; Saffon-Merceron, N.; Rodriguez, F.; Lherbet, C.; Belkheiri, N.; Amari, M.; Hoffmann, P.; Fodili, M. Evaluation of heteroatom-rich derivatives as antitubercular agents with inhA inhibition properties. Med. Chem. Res., 2018, 27(1), 308-320.
[http://dx.doi.org/10.1007/s00044-017-2064-x]
[63]
Slepikas, L.; Chiriano, G.; Perozzo, R.; Tardy, S.; Kranjc, A.; Patthey-Vuadens, O.; Ouertatani-Sakouhi, H.; Kicka, S.; Harrison, C.F.; Scrignari, T.; Perron, K.; Hilbi, H.; Soldati, T.; Cosson, P.; Tarasevicius, E.; Scapozza, L. In silico driven design and synthesis of rhodanine derivatives as novel antibacterials targeting the enoyl reductase InhA. J. Med. Chem., 2016, 59(24), 10917-10928.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01620] [PMID: 26730986]

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