The Open Medicinal Chemistry Journal




ISSN: 1874-1045 ― Volume 15, 2021
RESEARCH ARTICLE

Antitumor Activity In Vitro Provided by N-Alkyl-Nitroimidazole Compounds



Janny A. Villa-Pulgarin1, Constain H. Salamanca2, Jose Oñate-Garzón3, Ruben E Varela-M3, *
1 Grupo de Investigaciones Biomédicas, Facultad de Ciencias de la Salud, Corporación Universitaria Remington, Calle 51 No 51-27 Medellín, Colombia.
2 Laboratorio de Diseño y Formulación de Productos Químicos y Derivados, Departamento de Ciencias Farmacéuticas, Facultad de Ciencias Naturales, Universidad ICESI, Calle 18 No. 122 -135, Cali, 760035, Colombia.
3 Grupo de Investigación en Química y Biotecnología (QUIBIO), Facultad de Ciencias Básicas, Universidad Santiago de Cali, calle 5 No. 62-00, Cali 760035, Colombia.

Abstract

Background:

Cancer is one of the most common diseases in the world, with over 18 million new cases estimated in 2018. Many of the drugs used for cancer can have significant adverse effects and variable effectiveness. Nitroimidazoles are prodrugs that usually have shown antimicrobial activity specifically antiparasitic. However, its antitumor activity in vitro has barely been explored.

Objective:

The aim of this study is to determine the influence of the length of the substituted N-alkyl chain in the imidazole ring on the antitumor activity in vitro.

Methods:

Four nitroimidazoles were obtained by chemical synthesis varying the length of the substituted N-alkyl chain from methyl to butyl. The antitumor activity of N-alkyl-nitroimidazoles was evaluated by MTT assay employing two tumor cell lines (MDA-MB231 and A549).

Results:

In this study, it was reported that N-alkyl nitroimidazoles exhibited an LC50 as low as 16.7 µM in breast tumor cells MDA-MB231 while in normal Vero kidney cells, the LC50 was around 30 µM. It was also reported that the length of the substituted N-Alkyl chain in the imidazole ring affects the antitumoral activity in A549 lung cells.

Conclusion:

Increasing the length of the substituted N-Alkyl chain in the imidazole ring decreased the antitumor activity against only A549 cancer cells. N-alkyl nitroimidazoles exhibited considerable selectivity towards tumor cell lines.

Keywords: N-Alkyl-Nitroimidazole, Chain length, Antitumor activity, MTT assay, Breast and lung cancer cells, Tumor cells MDA-MB231.


Article Information


Identifiers and Pagination:

Year: 2020
Volume: 14
First Page: 45
Last Page: 48
Publisher Id: TOMCJ-14-45
DOI: 10.2174/1874104502014010045

Article History:

Received Date: 29/03/2020
Revision Received Date: 05/06/2020
Acceptance Date: 22/06/2020
Electronic publication date: 30/07/2020
Collection year: 2020

© 2020 Villa-Pulgarin etal.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Grupo de Investigación en Química y Biotecnología (QUIBIO), Facultad de Ciencias Básicas, Universidad Santiago de Cali, calle 5 No. 62-00, Cali 760035, Colombia Tel:+57-2-5183000, E-mail: ruben.varela00@usc.edu.co





1. INTRODUCTION

Cancer is considered a public health problem worldwide and in Colombia. According to the International Agency for Research on Cancer, it is estimated that there were 18.1 million new cancer cases and 9.6 million cancer deaths in 2018 [1Global Cancer Observatory Chile - Globocan 2018. Glob. Cancer Obs, 2018.,2Torre, L.A.; Trabert, B.; DeSantis, C.E.; Miller, K.D.; Samimi, G.; Runowicz, C.D.; Gaudet, M.M.; Jemal, A.; Siegel, R.L. Ovarian cancer statistics, 2018. CA Cancer J. Clin., 2018, 68(4), 284-296.
[http://dx.doi.org/10.3322/caac.21456] [PMID: 29809280]
]. The most commonly diagnosed cancer is lung cancer in men and breast cancer in women [3Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
]. Due to the high number ofcases that occur, the large number of adverse effects and the low effectiveness that is achieved in many of the treatments, it is of great importance for many organizations to investigate new alternatives for their treatment. The current treatment modalities are surgical resection, radiation therapy, hormone therapy, anti-hormone therapy, combined therapy as chemotherapy and radiation therapy, where the most commonly used chemotherapeutic agents are cytotoxic agents for cancer cells [4Khan, T.; Date, A.; Chawda, H.; Patel, K. Polysaccharides as potential anticancer agents-A review of their progress. Carbohydr. Polym., 2019, 210, 412-428.
[http://dx.doi.org/10.1016/j.carbpol.2019.01.064] [PMID: 30732778]
]. Some of these agents correspond to the imidazole compounds, which are developed towards their application in medicinal chemistry due to their pharmacological properties, such as anticancer activity with high efficacy and low toxicity [5Bistrović, A.; Krstulović, L.; Harej, A.; Grbčić, P.; Sedić, M.; Koštrun, S.; Pavelić, S.K.; Bajić, M.; Raić-Malić, S. Design, synthesis and biological evaluation of novel benzimidazole amidines as potent multi-target inhibitors for the treatment of non-small cell lung cancer. Eur. J. Med. Chem., 2018, 143, 1616-1634.
[http://dx.doi.org/10.1016/j.ejmech.2017.10.061] [PMID: 29133046]
,6Kumar, S.; Saha, S.T.; Gu, L.; Palma, G.; Perumal, S.; Singh-Pillay, A.; Singh, P.; Anand, A.; Kaur, M.; Kumar, V. 1H-1,2,3-Triazole Tethered Nitroimidazole-Isatin Conjugates: Synthesis, Docking, and Anti-Proliferative Evaluation against Breast Cancer. ACS Omega, 2018, 3(9), 12106-12113.
[http://dx.doi.org/10.1021/acsomega.8b01513] [PMID: 30320289]
]. In this context, the imidazole ring containing two nitrogen atoms and desirable π-conjugated backbone can interfere with DNA synthesis, altering enzymes involved in DNA replication and the expression of genes associated with cancer cell growth such as tumor suppressor and cell cycle genes [7Zhang, L.; Peng, X.M.; Damu, G.L.V.; Geng, R.X.; Zhou, C.H. Comprehensive review in current developments of imidazole-based medicinal chemistry. Med. Res. Rev., 2014, 34(2), 340-437.
[http://dx.doi.org/10.1002/med.21290] [PMID: 23740514]
]. There are enough studies where imidazole ring is combined with heteroatom-containing groups in a single compound in order to generate compounds with improved anticancer activity [7Zhang, L.; Peng, X.M.; Damu, G.L.V.; Geng, R.X.; Zhou, C.H. Comprehensive review in current developments of imidazole-based medicinal chemistry. Med. Res. Rev., 2014, 34(2), 340-437.
[http://dx.doi.org/10.1002/med.21290] [PMID: 23740514]
]. Previous studies have reported that N-alkyl imidazoles display potent anticancer activity via inhibition heme oxygenase (HO-1 and HO-2), an enzyme related to certain types of cancers [8Kontogiorgis, C.; Hadjipavlou-Litina, D. Thromboxane synthase inhibitors and thromboxane A2 receptor antagonists: a quantitative structure activity relationships (QSARs) analysis. Curr. Med. Chem., 2010, 17(28), 3162-3214.
[http://dx.doi.org/10.2174/092986710792231978] [PMID: 20666724]
,9Sorrenti, V.; Guccione, S.; Di Giacomo, C.; Modica, M.N.; Pittalà, V.; Acquaviva, R.; Basile, L.; Pappalardo, M.; Salerno, L. Evaluation of imidazole-based compounds as heme oxygenase-1 inhibitors. Chem. Biol. Drug Des., 2012, 80(6), 876-886.
[http://dx.doi.org/10.1111/cbdd.12015] [PMID: 22882835]
].

On the other hand, the length of the alkyl chain on the imidazole ring is relevant for antimicrobial activity. Khabnadideh et al., 2003 [10Khabnadideh, S.; Rezaei, Z.; Khalafi-Nezhad, A.; Bahrinajafi, R.; Mohamadi, R.; Farrokhroz, A.A. Synthesis of N-alkylated derivatives of imidazole as antibacterial agents. Bioorg. Med. Chem. Lett., 2003, 13(17), 2863-2865.
[http://dx.doi.org/10.1016/S0960-894X(03)00591-2] [PMID: 14611845]
] showed that antibacterial activity of 1-alkylimidazoles against Gram-negative and Gram-positive bacteria increases, as the number of carbons in the alkyl chain rises up to nine and then decreases. However, the knowledge about the contributions of the number of carbons in the acyl chain on anticancer activity is reduced. N-alkyl-nitroimidazoles with different carbon numbers in the alkyl chain were synthesized and theoretically studied in previous research [11Salamanca, M.C.; Tiznado, V.W.; Jaramillo, G.P. Estudio experimental y teórico de la síntesis de N-alquil-nitroimidazoles. Vitae, 2010, 17, 199-208.]. Herein, we describe the effect of the alkyl chain length substituted in the N-imidazole ring on the anticancer activity against cell lines A549 (Human lung carcinoma) and MDA-MB-231 (Human breast adenocarcinoma).

2. MATERIALS AND METHODS

The N-alkyl-nitroimidazoles used in this study were previously synthesized, characterized, cryopreserved (-20 ° C) and supplied by the laboratory of design and formulation of the Icesi University [11Salamanca, M.C.; Tiznado, V.W.; Jaramillo, G.P. Estudio experimental y teórico de la síntesis de N-alquil-nitroimidazoles. Vitae, 2010, 17, 199-208.], which were used as received. The human cancer cell lines A549 (Human lung carcinoma) and MDA-MB-231 (Human breast adenocarcinoma) were obtained from the American Type Culture Collection (ATCC). The cells were cultured in culture flasks with DMEM (Gibco, Life Technologies Corporation), supplemented with 10% FBS and penicillin (100 U/mL) and streptomycin (100 µg/mL) and were kept in a humidified incubator containing 5% CO2 at 37°C.

2.1. Cell Growth Inhibition Assay

Cell proliferation and viability were assessed by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) assay, through MTT conversion into colored formazan product by metabolically active cells [12Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
]. Cells (1,5 x 103 in 100 μL in 96-well flat-bottomed microliter plates) were incubated in DMEM culture medium containing 10% heat-inactivated FBS and were permitted to adhere for 12 h. After the culture medium was removed, 100 µL of different concentrations of nitroimidazoles (1, 5, 10, 25, 50 and 100 µM), prepared in DMEM, were added to each well. Following 48 h of incubation at 37ºC in a humidified atmosphere of air/CO2 (19/1), the MTT assay was performed. Measurements were done in triplicate. Absorbance was measured using an IMARKTM reader with a reference filter at 630 nm and a reading filter at 570 nm. The fraction of viable cells was calculated relative to control cells based on the following equation: (A1/A2) 100%, where A1 and A2 represent the absorbance of the sample and control groups, respectively. Each determination was performed in triplicate.

3. RESULTS

The in vitro antitumor activity for compounds was determined by the measurement of their cytostatic and cytotoxic properties in human tumor cell lines by MTT assays. The human cell lines used were MDA-MB-231 (human breast adenocarcinoma) and A549 (human lung carcinoma). As shown in Table 1, both breast cancer cells and lung cancer cells are sensitive to the compounds used; however, lung cancer cells were more sensitive to N-methyl-nitroimidazole and N-ethyl-nitroimidazole. Furthermore, the length of the alkyl chain influenced on the antitumoral activity against only A549 cell lines. As can be seen, all the compounds showed less activity against normal cells, as are Vero cells. Doxorubicin used as a positive control rendered IC50 values in the order of 10−7–10−8 M (data not shown).

In order to determine which of N-alkyl-nitroimidazole compounds displayed a higher cytotoxic activity, cell viability was evaluated, through the incorporation MTT assay A concentration-response curve was observed between concentration and viability. A decrease in the viability of both cancer cell lines regarding the increase in the N-alkyl-nitroimidazole concentration was evaluated and is depicted in Fig. (1). The results showed that the four N-alkyl-nitroimidazole compounds described greater activity against breast cancer than against lung cancer, where the N-methyl-nitroimidazole and N-ethyl-nitroimidazole compounds corresponded to those with the highest cytotoxic activity. (Fig. 1).

Table 1
In vitro growth inhibitory activity of compounds on normal and tumor cells.


Fig. (1)
Cell viability analysis. The viability of the cell lines exposed to different concentrations of the compounds was evaluated by MTT assay. In the figure, it was observed (A) breast cancer and (B) lung cancer. Data are means ± SD or representative of three independent experiments.


4. DISCUSSION

Anticancer activity measured as the LC50 in cancer cell lines decreased as the length of the substituted N-alkyl chain increased, solely for the A549 cell line. Regarding the MDA-MB231 cell line, the anticancer activity did not vary considerably when the length of the alkyl chain increased, suggesting that the number of carbons in the substituted N-alkyl did not influence on the activity against this type of cell.

There are several studies where the antibacterial and antiparasitic activity of nitroimidazoles is described [13–18Mital, A. Synthetic nitroimidazoles: Biological activities and mutagenicity relationships. Sci. Pharm., 2009, 77, 497-520.
[http://dx.doi.org/10.3797/scipharm.0907-14]
]. Al-Masoudi et al., reported that nitroimidazoles synthesized by a simple method exhibited some cytostatic activity against leukemia and melanoma cell lines [19Al-Masoudi, N.A.; Al-Soud, Y.A.; Kalogerakis, A.; Pannecouque, C.; De Clercq, E. Nitroimidazoles, part 2: Synthesis, antiviral and antitumor activity of new 4-nitroimidazoles. Chem. Biodivers., 2006, 3(5), 515-526.
[http://dx.doi.org/10.1002/cbdv.200690055] [PMID: 17193287]
]. In a previous study, nitroimidazole derivative of polypyridyl ruthenium complex was employed in order to evaluate the anticancer activity against breast cancer (4T1) and A549 cell lines and they reported that the tested cell lines were strongly inhibited with IC50 ranging from 1.5 to 18.8 µM [20Mazuryk, O.; Suzenet, F.; Kieda, C.; Brindell, M. The biological effect of the nitroimidazole derivative of a polypyridyl ruthenium complex on cancer and endothelial cells. Metallomics, 2015, 7(3), 553-566.
[http://dx.doi.org/10.1039/C5MT00037H] [PMID: 25711770]
], a range covering the LC50 values exhibited by N-methyl and N-ethyl-nitroimidazoles. In a study conducted by Kumar et al., 1H-1,2,3-Triazole Tethered Nitroimidazole−Isatin Conjugates showed IC50s of 54.25 and 26.12 μM against MCF-7 and MDA-MB-231 cell lines, respectively, when a butyl alkyl chain length as a spacer and a halogen-substituent on the isatin ring was placed [6Kumar, S.; Saha, S.T.; Gu, L.; Palma, G.; Perumal, S.; Singh-Pillay, A.; Singh, P.; Anand, A.; Kaur, M.; Kumar, V. 1H-1,2,3-Triazole Tethered Nitroimidazole-Isatin Conjugates: Synthesis, Docking, and Anti-Proliferative Evaluation against Breast Cancer. ACS Omega, 2018, 3(9), 12106-12113.
[http://dx.doi.org/10.1021/acsomega.8b01513] [PMID: 30320289]
]. LC50 values reported in our study are below those reported by Kumar et al. in MDA-MB-231 cell lines. Interestingly, Kumar et al., reported that the activity tends to increase with the increase in chain length in contrast with our results where activity decreased and was maintained with increasing chain length, against A549 and MDA-MB-231 cell lines, respectively. Furthermore, unlike our results, another study has reported that anticancer activity increases with the increase in the alkyl chain at imidazolium-based ionic liquids [21Malhotra, S. V.; Kumar, V. A profile of the in vitro anti-tumor activity of imidazolium-based ionic liquids. Bioorganic Med. Chem. Lett., 2010.], suggesting an interesting and poorly reported finding that could be explored in subsequent studies.

Here, the results also suggest a high selectivity of N-alkyl-nitroimidazoles toward cancer cells. Potential targets can be provided from imidazole derivatives to understand such selectivity. Heme oxygenase, an enzyme involved in the heme group catabolism, has been associated with the proliferation of A549 cancer cell line [22Kuroda, H.; Takeno, M.; Murakami, S.; Miyazawa, N.; Kaneko, T.; Ishigatsubo, Y. Inhibition of heme oxygenase-1 with an epidermal growth factor receptor inhibitor and cisplatin decreases proliferation of lung cancer A549 cells. Lung Cancer, 2010, 67(1), 31-36.
[http://dx.doi.org/10.1016/j.lungcan.2009.03.015] [PMID: 19375813]
] and has been identified as a selective target for functional groups such as azolyl moiety, phenyl groups, and alkyl linkages [23Vlahakis, J.Z.; Lazar, C.; Roman, G.; Vukomanovic, D.; Nakatsu, K.; Szarek, W.A. Heme oxygenase inhibition by α-(1H-imidazol-1-yl)-ω-phenylalkanes: effect of introduction of heteroatoms in the alkyl linker. ChemMedChem, 2012, 7(5), 897-902.
[http://dx.doi.org/10.1002/cmdc.201100602] [PMID: 22431362]
]. Another selective target of imidazole derivatives towards tumor cells is the cRAF-kinase protein, which is up-regulated in melanomas and alteration of this signaling protein would play a major role in melanoma progression [24Lee, J.; Kim, H.; Yu, H.; Chung, J.Y.; Oh, C.H.; Yoo, K.H.; Sim, T.; Hah, J.M. Discovery and initial SAR of pyrimidin-4-yl-1H-imidazole derivatives with antiproliferative activity against melanoma cell lines. Bioorg. Med. Chem. Lett., 2010, 20(5), 1573-1577.
[http://dx.doi.org/10.1016/j.bmcl.2010.01.064] [PMID: 20149658]
,25Smalley, K.S.M. A pivotal role for ERK in the oncogenic behaviour of malignant melanoma? Int. J. Cancer, 2003, 104(5), 527-532.
[http://dx.doi.org/10.1002/ijc.10978] [PMID: 12594806]
]. DNA is also known as another anticancer action target for imidazole derivatives. Chen et al. [26Chen, S.B.; Tan, J.H.; Ou, T.M.; Huang, S.L.; An, L.K.; Luo, H.B.; Li, D.; Gu, L.Q.; Huang, Z.S. Pharmacophore-based discovery of triaryl-substituted imidazole as new telomeric G-quadruplex ligand. Bioorg. Med. Chem. Lett., 2011, 21(3), 1004-1009.
[http://dx.doi.org/10.1016/j.bmcl.2010.12.019] [PMID: 21211968]
] described that triaryl-substituted imidazole was a telomeric G-quadruplex ligand which alters telomere maintenance, a crucial event for the unlimited proliferative potential of cancer cells.

CONCLUSION

In conclusion, compounds with increased antitumor activity and low cytotoxic effect in normal cells, may become therapeutic candidates for the treatment of cancer. Here, N-alkyl nitroimidazoles showed a reduced LC50 in lung cancer cells A549 and breast cancer MDA-MB231, while in Vero kidney cells, the LC50 was almost double for the case of N-ethyl-nitroimidazole. Interestingly, only in lung tumor cells, the length of the N-alkyl chain of nitroimidazole is inversely proportional to the anticancer activity. Therefore, the pronounced selectivity of these compounds to tumor cells is a property that should be explored in future trials to contribute to the design of new drugs that can potentially be used in clinical practice.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Not applicable.

HUMAN AND ANIMAL RIGHTS

Not applicable.

CONSENT FOR PUBLICATION

Not applicable.

AVAILABILITY OF DATA AND MATERIALS

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The author declares no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

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[http://dx.doi.org/10.3797/scipharm.0907-14]
[19] Al-Masoudi, N.A.; Al-Soud, Y.A.; Kalogerakis, A.; Pannecouque, C.; De Clercq, E. Nitroimidazoles, part 2: Synthesis, antiviral and antitumor activity of new 4-nitroimidazoles. Chem. Biodivers., 2006, 3(5), 515-526.
[http://dx.doi.org/10.1002/cbdv.200690055] [PMID: 17193287]
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[http://dx.doi.org/10.1039/C5MT00037H] [PMID: 25711770]
[21] Malhotra, S. V.; Kumar, V. A profile of the in vitro anti-tumor activity of imidazolium-based ionic liquids. Bioorganic Med. Chem. Lett., 2010.
[22] Kuroda, H.; Takeno, M.; Murakami, S.; Miyazawa, N.; Kaneko, T.; Ishigatsubo, Y. Inhibition of heme oxygenase-1 with an epidermal growth factor receptor inhibitor and cisplatin decreases proliferation of lung cancer A549 cells. Lung Cancer, 2010, 67(1), 31-36.
[http://dx.doi.org/10.1016/j.lungcan.2009.03.015] [PMID: 19375813]
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"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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