Design, Synthesis and Antimycobacterial Activity of 2-(Benzimidazol-2-yl)-propanenitrile Analogs
Yıl 2022,
, 83 - 92, 01.06.2022
Oya Ünsal Tan
,
Mustafa Mert Sırım
Siva Krishna Vagolu
,
Sriram Dharmarajan
Öz
This paper reports the synthesis and evaluation of some new 2-(benzimidazol-2-yl)-3-(4-(4-substitutedpiperazin-1-yl)phenyl)propanenitrile derivatives for their in vitro antimycobacterial activities against Mycobacterium tuberculosis H37Rv. Among them, 4c was found to be the most active compound with MIC of 1.56 μg/mL against M. tuberculosis. In addition, 4c showed 2.1 log reduction against nutrient starved M. tuberculosis which is more potent than first line drugs. Based on their predicted physicochemical values, the compounds obeyed the Lipinski’s "rule of five," and TPSA/nROT limits. Molecular docking studies were performed to estimate the orientation of 4c at the active site of M. tuberculosis LAT enzyme. These results suggest that 4c may be a good candidate for drug development owing to potential against both active and dormant forms of M. tuberculosis.
Destekleyen Kurum
Hacettepe University
Proje Numarası
THD-2019-17927
Kaynakça
- (1) Dheda, K.; Barry, C. E.; Maartens, G. Tuberculosis. Lancet 2016, 387 (10024), 1211–1226. https://doi.org/10.1016/S0140-6736(15)00151-8.
- (2) Global Tuberculosis Report 2019; World Health Organization 2019, Ed.; 2019.
- (3) Gandhi, N. R.; Brust, J. C. M.; Shah, N. S. A New Era for Treatment of Drug-Resistant Tuberculosis. Eur. Respir. J. 2018, 52, 1801350. https://doi.org/10.1183/13993003.01350-2018.
- (4) Nahid, P.; Mase, S. R.; Migliori, G. B.; Sotgiu, G.; Bothamley, G. H.; Brozek, J. L. et al. Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline. Am. J. Respir. Crit. Care Med. 2019, 200 (10), e93–e142. https://doi.org/10.1164/rccm.201909-1874ST.
- (5) Blumberg, H. M.; Ernst, J. D. The Challenge of Latent TB Infection. JAMA 2016, 316 (9), 931–933. https://doi.org/10.1001/jama.2016.11021.
- (6) van den Boogaard, J.; Kibiki, G. S.; Kisanga, E. R.; Boeree, M. J.; Aarnoutse, R. E. New Drugs against Tuberculosis: Problems, Progress, and Evaluation of Agents in Clinical Development. Antimicrob. Agents Chemother. 2009, 53 (3), 849 LP – 862. https://doi.org/10.1128/AAC.00749-08.
- (7) Tiberi, S.; Muñoz-Torrico, M.; Duarte, R.; Dalcolmo, M.; D’Ambrosio, L.; Migliori, G.-B. New Drugs and Perspectives for New Anti-Tuberculosis Regimens. Pulmonology 2018, 24 (2), 86–98. https://doi.org/10.1016/j.rppnen.2017.10.009.
- (8) Akhtar, W.; Khan, M. F.; Verma, G.; Shaquiquzzaman, M.; Rizvi, M. A.; Mehdi, S. H.; Akhter, M.; Alam, M. M. Therapeutic Evolution of Benzimidazole Derivatives in the Last Quinquennial Period. Eur. J. Med. Chem. 2017, 126, 705–753. https://doi.org/https://doi.org/10.1016/j.ejmech.2016.12.010.
- (9) Keri, R. S.; Hiremathad, A.; Budagumpi, S.; Nagaraja, B. M. Comprehensive Review in Current Developments of Benzimidazole-Based Medicinal Chemistry. Chem. Biol. Drug Des. 2015, 86 (1), 19–65. https://doi.org/10.1111/cbdd.12462.
- (10) Surineni, G.; Gao, Y.; Hussain, M.; Liu, Z.; Lu, Z.; Chhotaray, C.; Islam, M. M.; Hameed, H. M. A.; Zhang, T. Design, Synthesis, and in Vitro Biological Evaluation of Novel Benzimidazole Tethered Allylidenehydrazinylmethylthiazole Derivatives as Potent Inhibitors of Mycobacterium Tuberculosis. Medchemcomm 2019, 10 (1), 49–60. https://doi.org/10.1039/C8MD00389K.
- (11) Chandrasekera, N. S.; Berube, B. J.; Shetye, G.; Chettiar, S.; O’Malley, T.; Manning, A.; Flint, L.; Awasthi, D.; Ioerger, T. R.; Sacchettini, J.; Masquelin, T.; Hipskind, P. A.; Odingo, J.; Parish, T. Improved Phenoxyalkylbenzimidazoles with Activity against Mycobacterium Tuberculosis Appear to Target QcrB. ACS Infect. Dis. 2017, 3 (12), 898–916. https://doi.org/10.1021/acsinfecdis.7b00112.
- (12) Gobis, K.; Foks, H.; Serocki, M.; Augustynowicz-Kopeć, E.; Napiórkowska, A. Synthesis and Evaluation of in Vitro Antimycobacterial Activity of Novel 1H-Benzo[d]Imidazole Derivatives and Analogues. Eur. J. Med. Chem. 2015, 89, 13–20. https://doi.org/https://doi.org/10.1016/j.ejmech.2014.10.031.
- (13) Awasthi, D.; Kumar, K.; Knudson, S. E.; Slayden, R. A.; Ojima, I. SAR Studies on Trisubstituted Benzimidazoles as Inhibitors of Mtb FtsZ for the Development of Novel Antitubercular Agents. J. Med. Chem. 2013, 56, 9756–9770. https://doi.org/10.1021/jm401468w.
- (14) Bose, P.; Harit, A. K.; Das, R.; Sau, S.; Iyer, A. K.; Kashaw, S. K. Tuberculosis: Current Scenario, Drug Targets, and Future Prospects. Med. Chem. Res. 2021. https://doi.org/10.1007/s00044-020-02691-5.
- (15) Sirim, M. M.; Krishna, V. S.; Sriram, D.; Unsal Tan, O. Novel Benzimidazole-Acrylonitrile Hybrids and Their Derivatives: Design, Synthesis and Antimycobacterial Activity. Eur. J. Med. Chem. 2020, 188, 112010. https://doi.org/https://doi.org/10.1016/j.ejmech.2019.112010.
- (16) Meciarova, M.; Toma, S.; Magdolen, P. Ultrasound Effect on the Aromatic Nucleophilic Substitution Reactions on Some Haloarenes. Ultrason. Sonochem. 2003, 10 (4–5), 265–270. https://doi.org/10.1016/S1350-4177(02)00157-8.
- (17) 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. 1997, 23 (1), 3–25. https://doi.org/https://doi.org/10.1016/S0169-409X(96)00423-1.
- (18) Muchmore, S. W.; Edmunds, J. J.; Stewart, K. D.; Hajduk, P. J. Cheminformatic Tools for Medicinal Chemists. J. Med. Chem. 2010, 53 (13), 4830–4841. https://doi.org/10.1021/jm100164z.
- (19) Veber, D. F.; Johnson, S. R.; Cheng, H.-Y.; Smith, B. R.; Ward, K. W.; Kopple, K. D. Molecular Properties That Influence the Oral Bioavailability of Drug Candidates. J. Med. Chem. 2002, 45 (12), 2615–2623. https://doi.org/10.1021/jm020017n.
- (20) Devi, P. B.; Sridevi, J. P.; Kakan, S. S.; Saxena, S.; Jeankumar, V. U.; Soni, V.; Anantaraju, H. S.; Yogeeswari, P.; Sriram, D. Discovery of Novel Lysine Ɛ-Aminotransferase Inhibitors: An Intriguing Potential Target for Latent Tuberculosis. Tuberculosis 2015, 95 (6), 786–794. https://doi.org/https://doi.org/10.1016/j.tube.2015.04.010.
- (21) Murphy, D. J.; Brown, J. R. Identification of Gene Targets against Dormant Phase Mycobacterium Tuberculosis Infections. BMC Infect. Dis. 2007, 7 (1), 84. https://doi.org/10.1186/1471-2334-7-84.
- (22)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.
- (23) Betts, J. C.; Lukey, P. T.; Robb, L. C.; McAdam, R. A.; Duncan, K. Evaluation of a Nutrient Starvation Model of Mycobacterium Tuberculosis Persistence by Gene and Protein Expression Profiling. Mol. Microbiol. 2002, 43 (3), 717–731. https://doi.org/10.1046/j.1365-2958.2002.02779.x.
- (24) Malapati, P.; Siva Krishna, V.; Nallangi, R.; Meda, N.; Reshma Srilakshmi, R.; Sriram, D. Lead Identification and Optimization of Bacterial Glutamate Racemase Inhibitors. Bioorg. Med. Chem. 2018, 26 (1), 177–190. https://doi.org/https://doi.org/10.1016/j.bmc.2017.11.031.
Yıl 2022,
, 83 - 92, 01.06.2022
Oya Ünsal Tan
,
Mustafa Mert Sırım
Siva Krishna Vagolu
,
Sriram Dharmarajan
Öz
Bu makale, Mycobacterium tuberculosis H37Rv'ye karşı in vitro antimikobakteriyel aktiviteleri için bazı yeni 2-(benzimidazol-2-yl)-3-(4-(4-substitüepiperazin-1-yl)fenil)propannitril türevlerinin sentezini ve aktivitelerinin değerlendirilmesini içermektedir. Bileşikler arasında M. tuberculosis'e karşı 1.56 μg/mL MIC değeri ile en aktif bileşik 4c olarak bulundu. Ek olarak, 4c, besin açlık modeli testinde 2.1 log azalma sağlayarak birinci basamak ilaçlardan daha güçlü antimikobakteriyel aktivite göstermiştir. Hesaplanan fizikokimyasal değerlere dayanarak, bileşiklerin Lipinski'nin "beşler kuralına" ve TPSA/nROT limitlerine uyduğu tahmin edilmektedir. 4c'nin M. tuberculosis LAT enziminin aktif bölgesindeki oryantasyonunu tahmin etmek için moleküler yerleştirme çalışmaları yapıldı. Bu sonuçlar, M. tuberculosis'in hem aktif hem de latent formlarına karşı potansiyeli nedeniyle 4c'nin ilaç geliştirme için iyi bir aday olabileceğini düşündürmektedir.
Proje Numarası
THD-2019-17927
Kaynakça
- (1) Dheda, K.; Barry, C. E.; Maartens, G. Tuberculosis. Lancet 2016, 387 (10024), 1211–1226. https://doi.org/10.1016/S0140-6736(15)00151-8.
- (2) Global Tuberculosis Report 2019; World Health Organization 2019, Ed.; 2019.
- (3) Gandhi, N. R.; Brust, J. C. M.; Shah, N. S. A New Era for Treatment of Drug-Resistant Tuberculosis. Eur. Respir. J. 2018, 52, 1801350. https://doi.org/10.1183/13993003.01350-2018.
- (4) Nahid, P.; Mase, S. R.; Migliori, G. B.; Sotgiu, G.; Bothamley, G. H.; Brozek, J. L. et al. Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline. Am. J. Respir. Crit. Care Med. 2019, 200 (10), e93–e142. https://doi.org/10.1164/rccm.201909-1874ST.
- (5) Blumberg, H. M.; Ernst, J. D. The Challenge of Latent TB Infection. JAMA 2016, 316 (9), 931–933. https://doi.org/10.1001/jama.2016.11021.
- (6) van den Boogaard, J.; Kibiki, G. S.; Kisanga, E. R.; Boeree, M. J.; Aarnoutse, R. E. New Drugs against Tuberculosis: Problems, Progress, and Evaluation of Agents in Clinical Development. Antimicrob. Agents Chemother. 2009, 53 (3), 849 LP – 862. https://doi.org/10.1128/AAC.00749-08.
- (7) Tiberi, S.; Muñoz-Torrico, M.; Duarte, R.; Dalcolmo, M.; D’Ambrosio, L.; Migliori, G.-B. New Drugs and Perspectives for New Anti-Tuberculosis Regimens. Pulmonology 2018, 24 (2), 86–98. https://doi.org/10.1016/j.rppnen.2017.10.009.
- (8) Akhtar, W.; Khan, M. F.; Verma, G.; Shaquiquzzaman, M.; Rizvi, M. A.; Mehdi, S. H.; Akhter, M.; Alam, M. M. Therapeutic Evolution of Benzimidazole Derivatives in the Last Quinquennial Period. Eur. J. Med. Chem. 2017, 126, 705–753. https://doi.org/https://doi.org/10.1016/j.ejmech.2016.12.010.
- (9) Keri, R. S.; Hiremathad, A.; Budagumpi, S.; Nagaraja, B. M. Comprehensive Review in Current Developments of Benzimidazole-Based Medicinal Chemistry. Chem. Biol. Drug Des. 2015, 86 (1), 19–65. https://doi.org/10.1111/cbdd.12462.
- (10) Surineni, G.; Gao, Y.; Hussain, M.; Liu, Z.; Lu, Z.; Chhotaray, C.; Islam, M. M.; Hameed, H. M. A.; Zhang, T. Design, Synthesis, and in Vitro Biological Evaluation of Novel Benzimidazole Tethered Allylidenehydrazinylmethylthiazole Derivatives as Potent Inhibitors of Mycobacterium Tuberculosis. Medchemcomm 2019, 10 (1), 49–60. https://doi.org/10.1039/C8MD00389K.
- (11) Chandrasekera, N. S.; Berube, B. J.; Shetye, G.; Chettiar, S.; O’Malley, T.; Manning, A.; Flint, L.; Awasthi, D.; Ioerger, T. R.; Sacchettini, J.; Masquelin, T.; Hipskind, P. A.; Odingo, J.; Parish, T. Improved Phenoxyalkylbenzimidazoles with Activity against Mycobacterium Tuberculosis Appear to Target QcrB. ACS Infect. Dis. 2017, 3 (12), 898–916. https://doi.org/10.1021/acsinfecdis.7b00112.
- (12) Gobis, K.; Foks, H.; Serocki, M.; Augustynowicz-Kopeć, E.; Napiórkowska, A. Synthesis and Evaluation of in Vitro Antimycobacterial Activity of Novel 1H-Benzo[d]Imidazole Derivatives and Analogues. Eur. J. Med. Chem. 2015, 89, 13–20. https://doi.org/https://doi.org/10.1016/j.ejmech.2014.10.031.
- (13) Awasthi, D.; Kumar, K.; Knudson, S. E.; Slayden, R. A.; Ojima, I. SAR Studies on Trisubstituted Benzimidazoles as Inhibitors of Mtb FtsZ for the Development of Novel Antitubercular Agents. J. Med. Chem. 2013, 56, 9756–9770. https://doi.org/10.1021/jm401468w.
- (14) Bose, P.; Harit, A. K.; Das, R.; Sau, S.; Iyer, A. K.; Kashaw, S. K. Tuberculosis: Current Scenario, Drug Targets, and Future Prospects. Med. Chem. Res. 2021. https://doi.org/10.1007/s00044-020-02691-5.
- (15) Sirim, M. M.; Krishna, V. S.; Sriram, D.; Unsal Tan, O. Novel Benzimidazole-Acrylonitrile Hybrids and Their Derivatives: Design, Synthesis and Antimycobacterial Activity. Eur. J. Med. Chem. 2020, 188, 112010. https://doi.org/https://doi.org/10.1016/j.ejmech.2019.112010.
- (16) Meciarova, M.; Toma, S.; Magdolen, P. Ultrasound Effect on the Aromatic Nucleophilic Substitution Reactions on Some Haloarenes. Ultrason. Sonochem. 2003, 10 (4–5), 265–270. https://doi.org/10.1016/S1350-4177(02)00157-8.
- (17) 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. 1997, 23 (1), 3–25. https://doi.org/https://doi.org/10.1016/S0169-409X(96)00423-1.
- (18) Muchmore, S. W.; Edmunds, J. J.; Stewart, K. D.; Hajduk, P. J. Cheminformatic Tools for Medicinal Chemists. J. Med. Chem. 2010, 53 (13), 4830–4841. https://doi.org/10.1021/jm100164z.
- (19) Veber, D. F.; Johnson, S. R.; Cheng, H.-Y.; Smith, B. R.; Ward, K. W.; Kopple, K. D. Molecular Properties That Influence the Oral Bioavailability of Drug Candidates. J. Med. Chem. 2002, 45 (12), 2615–2623. https://doi.org/10.1021/jm020017n.
- (20) Devi, P. B.; Sridevi, J. P.; Kakan, S. S.; Saxena, S.; Jeankumar, V. U.; Soni, V.; Anantaraju, H. S.; Yogeeswari, P.; Sriram, D. Discovery of Novel Lysine Ɛ-Aminotransferase Inhibitors: An Intriguing Potential Target for Latent Tuberculosis. Tuberculosis 2015, 95 (6), 786–794. https://doi.org/https://doi.org/10.1016/j.tube.2015.04.010.
- (21) Murphy, D. J.; Brown, J. R. Identification of Gene Targets against Dormant Phase Mycobacterium Tuberculosis Infections. BMC Infect. Dis. 2007, 7 (1), 84. https://doi.org/10.1186/1471-2334-7-84.
- (22)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.
- (23) Betts, J. C.; Lukey, P. T.; Robb, L. C.; McAdam, R. A.; Duncan, K. Evaluation of a Nutrient Starvation Model of Mycobacterium Tuberculosis Persistence by Gene and Protein Expression Profiling. Mol. Microbiol. 2002, 43 (3), 717–731. https://doi.org/10.1046/j.1365-2958.2002.02779.x.
- (24) Malapati, P.; Siva Krishna, V.; Nallangi, R.; Meda, N.; Reshma Srilakshmi, R.; Sriram, D. Lead Identification and Optimization of Bacterial Glutamate Racemase Inhibitors. Bioorg. Med. Chem. 2018, 26 (1), 177–190. https://doi.org/https://doi.org/10.1016/j.bmc.2017.11.031.