Design, Synthesis and Antitubercular Activity of Certain Nicotinic Acid Hydrazides
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Evaluation
2.2.1. In Vitro Antimycobacterial Activity
Compound | Ar | R1 | R2 | R3 | Mean of Inhibition % | MIC (µg/mL) | LogP a | Drug-Likeness Model Score b | |
---|---|---|---|---|---|---|---|---|---|
4a | C6H5 | 42.52 ± 0.63 | 25 | 1.36 | −0.1 | ||||
4b | 4-CH3C6H4 | 36.33 ± 0.58 | 25 | 1.81 | −0.36 | ||||
4c | 4-FC6H4 | NA | NA | 1.53 | −0.06 | ||||
4d | 4-ClC6H4 | 12.45 ± 0.58 | 100 | 2.04 | 0.05 | ||||
4e | 4-BrC6H4 | 20.63 ± 0.63 | 50 | 2.17 | −0.25 | ||||
4f | 4-CH3OC6H4 | 42.63 ± 0.16 | 25 | 1.42 | −0.25 | ||||
4g | 3,4(CH3O)2C6H3 | 22.63 ± 0.16 | 50 | 1.01 | 0.13 | ||||
4h | 3,4,5(CH3O)3C6H2 | 18.32 ± 0.72 | 50 | 0.99 | 0.33 | ||||
4i | thiophen-2-yl | 22.63 ± 0.20 | 50 | 1.15 | −0.10 | ||||
7a | H | H | H | NA | NA | 4.95 | 0.12 | ||
7b | H | H | F | NA | NA | 5.11 | 0.00 | ||
7c | H | H | Cl | NA | NA | 5.63 | 0.09 | ||
7d | Cl | H | Cl | 13.57 ± 0.72 | 100 | 6.23 | 0.13 | ||
7e | H | H | MeO | NA | NA | 5.01 | 0.09 | ||
7f | H | -(CH)4- | 14.32 ± 0.58 | 100 | 6.13 | 0.46 | |||
8a | H | 31.44 ± 0.58 | 25 | 3.54 | 0.88 | ||||
8b | Cl | 52.63 ± 0.58 | 12.5 | 4.19 | 0.62 | ||||
8c | Br | 77.42 ± 0.93 | 6.25 | 4.32 | 0.41 | ||||
Pyrazinamid | 93.25 ± 0.63 | 3.21 | |||||||
Isoniazide | - | 0.75 |
2.2.2. Structure Activity Relationships (SAR)
2.2.3. In Vitro Cytotoxicity
Compound | IC50 (µM) | ||||
---|---|---|---|---|---|
HT-29 | PC-3 | A549 | HepG2 | MCF-7 | |
8a | >200 | >200 | >200 | >200 | >200 |
8b | >200 | >200 | >200 | >200 | >200 |
8c | >200 | >200 | >200 | >200 | >200 |
Doxorubicin | 7.3 ± 1.11 | 6.5 ± 1.07 | 7.6 ± 1.37 | 6.9 ± 2.05 | 6.1 ± 1.95 |
2.3. ADME Study
Compound | AlogP98 a | PSA_2D b | Solubility c | Solubility Level d | Absorption Level e | CYP2D6 f | CYP2D6 Probability g |
---|---|---|---|---|---|---|---|
4a | 1.419 | 67.912 | −2.578 | 3 | 0 | 0 | 0.306 |
4b | 1.905 | 67.912 | −3.087 | 3 | 0 | 1 | 0.772 |
4d | 2.083 | 67.912 | −3.496 | 3 | 0 | 1 | 0.831 |
4e | 2.167 | 67.912 | −3.57 | 3 | 0 | 1 | 0.712 |
4f | 1.402 | 76.842 | −2.838 | 3 | 0 | 1 | 0.722 |
4g | 1.386 | 85.772 | −3.101 | 3 | 0 | 0 | 0.366 |
4h | 1.37 | 94.702 | −3.353 | 3 | 0 | 0 | 0.316 |
4i | 1.145 | 67.912 | −2.546 | 3 | 0 | 0 | 0.158 |
7d | 5.839 | 52.695 | −6.834 | 1 | 1 | 0 | 0.287 |
7f | 5.419 | 52.695 | −6.647 | 1 | 0 | 0 | 0.306 |
8a | 3.048 | 82.806 | −4.835 | 2 | 0 | 0 | 0.485 |
8b | 3.713 | 82.806 | −5.608 | 2 | 0 | 0 | 0.415 |
8c | 3.797 | 82.806 | −5.682 | 2 | 0 | 0 | 0.495 |
3. Experimental Section
3.1. General Information
3.2. Synthesis
3.2.1. Ethyl 2-methyl-6-arylnicotinates 3a–i
3.2.2. 6-Aryl-2-methylnicotinohydrazides 4a–i
3.2.3. General Procedure for Synthesis of N′-arylidene-6-(4-bromophenyl)-2-methylnicotinyl Hydrazides 7a–f
3.2.4. General Procedure for Preparation of Target Compounds 8a–c
3.3. Biological Evaluation
3.3.1. Antimycobacterial Activity
3.3.2. In Vitro Cytotoxic Activity
4. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
- World Health Organization. Global Tuberculosis Report; WHO: Geneva, Switzerland, 2013. [Google Scholar]
- Zumla, A.; Nahid, P.; Cole, S.T. Advances in the development of new tuberculosis drugs and treatment regimens. Nat. Rev. Drug Discov. 2013, 12, 388–404. [Google Scholar] [CrossRef]
- Goldman, R.C.; Plumley, K.V.; Laughon, B.E. The evolution of extensively drug resistant tuberculosis (XDR-TB): History, status and issues for global control. Infect. Disord. Drug Targets 2007, 7, 73–91. [Google Scholar] [CrossRef] [PubMed]
- Benatar, S.R. Extensively drug resistant tuberculosis—Problem will get worse in South Africa unless poverty is alleviated. Br. Med. J. 2006, 333. [Google Scholar] [CrossRef]
- Lawn, S.D.; Wilkinson, R. Extensively drug resistant tuberculosis—A serious wake-up call for global health. Br. Med. J. 2006, 333, 559–560. [Google Scholar] [CrossRef]
- Dahle, U.R. Extensively drug resistant tuberculosis—Beware patients lost to follow-up. Br. Med. J. 2006, 333. [Google Scholar] [CrossRef]
- Gandhi, N.R.; Moll, A.; Sturm, A.W.; Pawinski, R.; Govender, T.; Lalloo, U.; Zeller, K.; Andrews, J.; Friedland, G. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006, 368, 1575–1580. [Google Scholar] [CrossRef] [PubMed]
- Manissero, D.; Fernandez, K. Extensive drug-resistant TB: A threat for Europe? Euro Surveill. 2006, 11, E060928. [Google Scholar] [PubMed]
- World Health Organization. Treatment of Tuberculosis Guidelines, 4th ed.; WHO: Geneva, Switzerland, 2010. [Google Scholar]
- Mitnick, C.D.; McGee, B.; Peloquin, C.A. Tuberculosis pharmacotherapy: Strategies to optimize patient Care. Expert. Opin. Pharmacother. 2009, 10, 381–401. [Google Scholar] [CrossRef] [PubMed]
- Domagk, G.; Offe, H.A.; Siefken, W. Ein weiterer Beitrag zur experimentellen Chemotherapie der Tuberkulose (Neoteben). Dtsch. Med. Wochenschr. 1952, 77, 573–578. [Google Scholar] [CrossRef] [PubMed]
- Janin, Y.L. Antituberculosis drugs: Ten years of research. Bioorg. Med. Chem. 2007, 15, 2479–2513. [Google Scholar] [CrossRef] [PubMed]
- Boechat, N.; Ferreira, V.F.; Ferreira, S.B.; Ferreira, M.G.; de C. da Silva, F.; Bastos, M.M.; dos S. Costa, M.; Lourenc, M.C.S.; Pinto, A.C.; Krettli, A.U.; et al. Novel 1,2,3-triazole derivatives for use against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain. J. Med. Chem. 2011, 54, 5988–5999. [Google Scholar] [CrossRef] [PubMed]
- Sandy, J.; Mushtaq, A.; Kawamura, A.; Sinclair, J.; Sim, E.; Noble, M. The Structure of Arylamine N-acetyltransferase from Mycobacterium smegmatis—An Enzyme which Inactivates the Antitubercular Drug, Isoniazid. J. Mol. Biol. 2002, 318, 1071–1083. [Google Scholar] [CrossRef] [PubMed]
- Lourençoa, M.C.S.; Ferreirab, M.L.; Souza, M.V.N.; Peralta, M.A.; Vasconcelos, T.R.A.; das Graças, M.; Henriques, M.O. Synthesis and antimycobacterial activity of (E)-N' (monosubstituted-benzylidene)isonicotinohydrazide derivatives. Eur. J. Med. Chem. 2008, 43, 1344–1347. [Google Scholar] [CrossRef] [PubMed]
- Cardoso, S.H.; de Assis, J.V.; de Almeida, M.V.; Lourenço, M.C.S.; Vicente, F.R.C.; de Souza, M.V.N. Synthesis and antitubercular activity of isoniazid condensed with carbohydrate derivatives. Quim. Nova 2009, 32, 1557–1560. [Google Scholar] [CrossRef]
- Bottari, B.; Maccari, R.; Monforte, F.; Ottana, R.; Rotondo, E.; Vigorita, M.G. Isoniazid-related copper(II) and nickel(II) complexes with antimycobacterial in vitro activity. part 9. Bioorg. Med. Chem. Lett. 2000, 10, 657–660. [Google Scholar] [CrossRef] [PubMed]
- Roye, W.E.; Ewart, G.E. A Preliminary Report on the Safety and Therapeutic Activity of a Salizid INH Derivative. Dis. Chest 1958, 33, 261–267. [Google Scholar] [CrossRef] [PubMed]
- Pershin, G.N.; Makeeva, O.O. Chemotherapeutic effect of phthivazide in experimental tuberculosis. Probl. Tuberk. 1953, 2, 16–20. [Google Scholar] [PubMed]
- Rubbo, S.D.; Edgar, J.; Vaughan, G. Chemotherapy of tuberculosis. I. Antituberculous activity of verazide and related hydrazones. Am. Rev. Tuberc. 1957, 76, 331–345. [Google Scholar] [PubMed]
- Soldatov, V.E. Saluzide in the treatment of tuberculous meningitis in adults. Probl. Tuberk. 1955, 6, 16–21. [Google Scholar] [PubMed]
- Judge, V.; Narasimhan, B.; Ahuja, M.; Sriram, D.; Yogeeswari, P.; Clercq, E.D.; Pannecouque, C.; Balzarini, J. Synthesis, antimycobacterial, antiviral, antimicrobial activities, and QSAR studies of isonicotinic acid-1-(substituted phenyl)-ethylidene/cycloheptylidene hydrazides. Med. Chem. Res. 2012, 21, 1935–1952. [Google Scholar] [CrossRef]
- Narang, R.; Narasimhan, B.; Sharma, S.; Sriram, D.; Yogeeswari, P.; Clercq, E.D.; Pannecouque, C.; Balzarini, J. Synthesis, antimycobacterial, antiviral, antimicrobial activities, and QSAR studies of nicotinic acid benzylidene hydrazide derivatives. Med. Chem. Res. 2012, 21, 1557–1576. [Google Scholar] [CrossRef]
- Eswaran, S.; Adhikari, A.V.; Pal, N.K.; Chowdhury, I.H. Design and synthesis of some new quinoline-3-carbohydrazone derivatives as potential antimycobacterial agents. Bioorg. Med. Chem. Lett. 2010, 20, 1040–1044. [Google Scholar] [CrossRef] [PubMed]
- Thomas, K.D.; Adhikari, A.V.; Telkar, S.; Chowdhury, I.H.; Mahmoode, R.; Pal, N.K.; Rowd, G.; Sumesh, E. Design, synthesis and docking studies of new quinoline-3-carbohydrazide derivatives as antitubercular agents. Eur. J. Med. Chem. 2011, 46, 5283–5292. [Google Scholar] [CrossRef]
- Aboul-Fadl, T.; Bin-Jubair, F.A.S.; Aboul-Wafa, O. Schiff bases of indoline-2,3-dione (isatin) derivatives and nalidixic acid carbohydrazide, synthesis, antitubercular activity and pharmacophoric model building. Eur. J. Med. Chem. 2010, 45, 4578–4586. [Google Scholar] [CrossRef] [PubMed]
- Feng, L.; Liu, M.; Zhang, S.; Chai, Y.; Wang, B.; Zhang, Y.; Lv, K.; Guan, Y.; Guo, H.; Xiao, C. Synthesis and in vitro antimycobacterial activity of 8-OCH3 ciprofloxacin methylene and ethylene isatin derivatives. Eur. J. Med. Chem. 2011, 46, 341–348. [Google Scholar] [CrossRef] [PubMed]
- Feng, L.; Liu, M.; Wang, B.; Chai, Y.; Hao, X.; Meng, S.; Guo, H. Synthesis and in vitro antimycobacterial activity of balofloxacin ethylene isatin derivatives. Eur. J. Med. Chem. 2010, 45, 3407–3412. [Google Scholar] [CrossRef] [PubMed]
- Sriram, D.; Yogeeswari, P.; Basha, J.S.; Radhab, D.R.; Nagaraja, V. Synthesis and antimycobacterial evaluation of various 7-substituted ciprofloxacin derivatives. Bioorg. Med. Chem. 2005, 13, 5774–5778. [Google Scholar] [CrossRef] [PubMed]
- AbouI-Fadl, T.; Mohammed, F.A.; Hassan, E.A. Synthesis, antitubercular activity and pharmacokinetic studies of some schiff bases derived from 1-alkylisatin and isonicotinic acid hydrazide (INH). Arch. Pharm. Res. 2003, 26, 778–784. [Google Scholar] [CrossRef] [PubMed]
- Collins, L.A.; 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, 1004–1009. [Google Scholar] [PubMed]
- Christensen, H.; Garton, N.; Harobin, R.; Minnikin, D.E.; Barer, M.R. Lipid domains of mycobacteria studied with fluorescent molecular probes. Mol. Microbiol. 1999, 31, 1561–1572. [Google Scholar] [CrossRef] [PubMed]
- Maccari, R.; Ottana, R.; Vigorita, M.G. In vitro advanced antimycobacterial screening of isoniazid-related hydrazones; hydrazides and cyanoboranes: Part 14. Bioorg. Med. Chem. Lett. 2005, 15, 2509–2513. [Google Scholar] [CrossRef] [PubMed]
- Hearn, M.J.; Cynamon, M.H. Design and synthesis of antituberculars: Preparation and evaluation against Mycobacterium tuberculosis of an isoniazid Schiff base. J. Antimicrob. Chemother. 2004, 53, 185–191. [Google Scholar] [CrossRef] [PubMed]
- Rodrigues, M.O.; Cantos, J.B.; D’Oca, C.R.; Soares, K.L.; Coelho, T.S.; Piovesan, L.A.; Russowsky, D.; da Silva, P.A.; D’Oca, M.G. Synthesis and antimycobacterial activity of isoniazid derivatives from renewable fatty acids. Bioorg. Med. Chem. 2005, 21, 6910–6914. [Google Scholar] [CrossRef]
- Vistoli, G.; Pedretti, A.; Testa, B. Assessing drug-likeness—What are we missing? Drug Discov. Today 2008, 13, 285–294. [Google Scholar] [CrossRef] [PubMed]
- Molinspiration Cheminformatics. Available online: http://www.molinspiration.com (accessed on 15 May 2015).
- Drug-Likeness and molecular property prediction. Available online: http://www.molsoft.com/mprop/ (accessed on 15 May 2015).
- Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J.T.; Bokesch, H.; Kenney, S.; Boyd, M.R. New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst. 1990, 82, 1107–1112. [Google Scholar] [CrossRef] [PubMed]
- Eldehna, W.M.; Altoukhy, A.; Mahrous, H.; Abdel-Aziz, H.A. Design, synthesis and QSAR study of certain isatin-pyridine hybrids as potential anti-proliferative agents. Eur. J. Med. Chem. 2015, 90, 684–694. [Google Scholar] [CrossRef] [PubMed]
- Al-Saleh, B.; Abdel-Khalik, M.M.; Eltoukhy, A.M.; Elnagdi, M.H. Enaminones in Heterocyclic Synthesis: A New Regioselective Synthesis of 2,3,6-Trisubstituted Pyridines, 6-Substituted-3-Aroylpyridines and 1,3,5-Triaroylbenzenes. J. Heterocycl. Chem. 2002, 39, 1035–1038. [Google Scholar] [CrossRef]
- Abdel-Aziz, H.A.; Aboul-Fadl, T.; Al-Obaid, A.M.; Ghazzali, M.; Al-Dhfyan, A.; Contini, A. Design, Synthesis and Pharmacophoric Model Building of Novel Substituted Nicotinic Acid Hydrazones with Potential Antiproliferative Activity. Arch. Pharm. Res. 2012, 35, 1543–1552. [Google Scholar] [CrossRef] [PubMed]
- Sample Availability: Not available.
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Eldehna, W.M.; Fares, M.; Abdel-Aziz, M.M.; Abdel-Aziz, H.A. Design, Synthesis and Antitubercular Activity of Certain Nicotinic Acid Hydrazides. Molecules 2015, 20, 8800-8815. https://doi.org/10.3390/molecules20058800
Eldehna WM, Fares M, Abdel-Aziz MM, Abdel-Aziz HA. Design, Synthesis and Antitubercular Activity of Certain Nicotinic Acid Hydrazides. Molecules. 2015; 20(5):8800-8815. https://doi.org/10.3390/molecules20058800
Chicago/Turabian StyleEldehna, Wagdy M., Mohamed Fares, Marwa M. Abdel-Aziz, and Hatem A. Abdel-Aziz. 2015. "Design, Synthesis and Antitubercular Activity of Certain Nicotinic Acid Hydrazides" Molecules 20, no. 5: 8800-8815. https://doi.org/10.3390/molecules20058800