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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Research Article

In Vitro, In Silico and Ex Vivo Studies of Dihydroartemisinin Derivatives as Antitubercular Agents

Author(s): Komal Kalani, Sarfaraz Alam, Vinita Chaturvedi, Shyam Singh, Feroz Khan and Santosh Kumar Srivastava*

Volume 19, Issue 8, 2019

Page: [633 - 644] Pages: 12

DOI: 10.2174/1568026619666190305131425

Price: $65

Abstract

Introduction: As a part of our drug discovery program for anti-tubercular agents, dihydroartemisinin (DHA-1) was screened against Mtb H37Rv, which showed moderate anti-tubercular activity (>25.0 µg/mL). These results prompted us to carry out the chemical transformation of DHA-1 into various derivatives and study their antitubercular potential.

Materials and Methods: DHA-1 was semi-synthetically converted into four new acyl derivatives (DHA-1A – DHA-1D) and in-vitro evaluated for their anti-tubercular potential against Mycobacterium tuberculosis H37Rv virulent strain. The derivatives, DHA-1C (12-O-(4-nitro) benzoyl; MIC 12.5 µg/mL) and DHA-1D (12-O-chloro acetyl; MIC 3.12µg/mL) showed significant activity against the pathogen.

Results: In silico studies of the most active derivative (DHA-1D) showed interaction with ARG448 inhibiting the mycobacterium enzymes. Additionally, it showed no cytotoxicity towards the Vero C1008 cells and Mouse bone marrow derived macrophages.

Conclusion: DHA-1D killed 62% intracellular M. tuberculosis in Mouse bone marrow macrophage infection model. To the best of our knowledge, this is the first-ever report on the antitubercular potential of dihydroartemisinin and its derivatives. Since dihydroartemisinin is widely used as an antimalarial drug; these results may be of great help in anti-tubercular drug development from a very common, inexpensive, and non-toxic natural product.

Keywords: Dihydroartemisinin, Semi-synthetic derivatives, Anti-tubercular activity, In-silico studies, Ex vivo studies, Multidrug-resistant TB.

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[1]
W. H. O. (2018). USA, . , 2018, p. 231.
[2]
Nguta, J.M.; Appiah-Opong, R.; Nyarko, A.K.; Yeboah-Manu, D.; Addo, P.G. Current perspectives in drug discovery against tuberculosis from natural products. Int. J. Mycobacteriol., 2015, 4(3), 165-183. [http://dx.doi.org/10.1016/j.ijmyco.2015.05.004]. [PMID: 27649863].
[3]
Quan, D.; Nagalingam, G.; Payne, R.; Triccas, J. A. Triccas. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2016, 56, 212-220.
[4]
Yi, F.; Li, L.; Xu, L.J.; Meng, H.; Dong, Y.M.; Liu, H.B.; Xiao, P.G. In silico approach in reveal traditional medicine plants pharmacological material basis. Chin. Med., 2018, 13, 33. [http://dx.doi.org/10.1186/s13020-018-0190-0]. [PMID: 29946351].
[5]
Ali, M.T.; Blicharska, N.; Shilpi, J.A.; Seidel, V. Investigation of the anti-TB potential of selected propolis constituents using a molecular docking approach. Sci. Rep., 2018, 8(1), 12238. [http://dx.doi.org/10.1038/s41598-018-30209-y]. [PMID: 30116003].
[6]
Ninad, V. Puranik, P. Srivastava, S. Swami, A. Choudhari, D. Sarkar. Molecular modeling studies and in vitro screening of dihydrorugosaflavonoid and its derivatives against Mycobacterium tuberculosis. RSC Advances, 2018, 8, 10634-10643.
[7]
Kalani, K.; Agarwal, J.; Alam, S.; Khan, F.; Pal, A.; Srivastava, S.K. In silico and in vivo anti-malarial studies of 18β glycyrrhetinic acid from Glycyrrhiza glabra. PLoS One, 2013, 8(9)e74761 [http://dx.doi.org/10.1371/journal.pone.0074761]. [PMID: 24086367].
[8]
Gupta, S.; Kalani, K.; Saxena, M.; Srivastava, S.K.; Agrawal, S.K.; Suri, N.; Saxena, A.K. Cytotoxic evaluation of semisynthetic ester and amide derivatives of oleanolic acid. Nat. Prod. Commun., 2010, 5(10), 1567-1570. [http://dx.doi.org/10.1177/ 1934578X1000501010]. [PMID: 21121249].
[9]
Tran Khac, V.; Nguyen Van, V.; Nguyen Van, T. A new route to novel 10-deoxoartemisinins. Tetrahedron Lett., 2005, 46, 4243-4245. [http://dx.doi.org/10.1016/j.tetlet.2005.04.042].
[10]
McClatchy, J.K. Susceptibility testing of mycobacteria. J. Lab. Med., 1978, 9, 47-52. [http://dx.doi.org/10.1093/labmed/9.3.47].
[11]
Kalani, K.; Chaturvedi, V.; Alam, S.; Khan, F.; Srivastava, S.K. Anti-tubercular agents from Glycyrrhiza glabra. Curr. Top. Med. Chem., 2015, 15(11), 1043-1049. [http://dx.doi.org/10.2174/ 1568026615666150317223323]. [PMID: 25786503].
[12]
Waterhouse, A.; Bertoni, M.; Bienert, S.; Studer, G.; Tauriello, G.; Gumienny, R.; Heer, F.T.; de Beer, T.A.P.; Rempfer, C.; Bordoli, L.; Lepore, R.; Schwede, T. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res., 2018, 46(W1), W296-W303. [http://dx.doi.org/10.1093/nar/gky427]. [PMID: 29788355].
[13]
Merget, B.; Zilian, T.; Müller, C.A. Sotriffer. In: Bioinformatics (Oxford, England);; , 2013; 29, pp. 62-68.
[14]
Alam, S.; Khan, F. QSAR and docking studies on xanthone derivatives for anticancer activity targeting DNA topoisomerase IIα. Drug Des. Devel. Ther., 2014, 8, 183-195. [PMID: 24516330].
[15]
Alam, S.; Khan, F. 3D-QSAR, Docking, ADME/Tox studies on Flavone analogs reveal anticancer activity through Tankyrase inhibition. Sci. Rep., 2019, 9(1), 5414. [http://dx.doi.org/10.1038/ s41598-019-41984-7]. [PMID: 30932078].
[16]
Merget, B.; Zilian, D.; Müller, T.; Sotriffer, C.A. MycPermCheck: the Mycobacterium tuberculosis permeability prediction tool for small molecules. Bioinformatics, 2013, 29(1), 62-68. [http://dx.doi.org/10.1093/bioinformatics/bts641]. [PMID: 23104888].
[17]
Ponnam, D.; Shilpi, S.; Srinivas, K.V.N.S.; Suiab, L.; Alam, S.; Amtul, Z.; Arigari, N.K.; Jonnala, K.K.; Siddiqui, L.; Dubey, V.; Tiwari, A.K.; Balasubramanian, S.; Khan, F. Synthesis of cyclic 1,9-acetal derivatives of forskolin and their bioactivity evaluation. Eur. J. Med. Chem., 2014, 87, 735-744. [http://dx.doi.org/10.1016/ j.ejmech.2014.10.013]. [PMID: 25305717].
[18]
Alam, S.; Khan, F. Virtual screening, docking, ADMET and system pharmacology studies on garcinia caged xanthone derivatives for anticancer activity. Sci. Rep., 2018, 8(1), 5524. [http://dx.doi.org/10.1038/s41598-018-23768-7]. [PMID: 29615704].
[19]
Chinthala, Y.; Thakur, S.; Tirunagari, S.; Chinde, S.; Domatti, A.K.; Arigari, N.K. S. K V N S, S.; Alam, K.K.; Jonnala, F.; Khan, A.; Tiwari, P. Grover. Eur. J. Med. Chem., 2015, 93, 564-573. [http://dx.doi.org/10.1016/j.ejmech.2015.02.027]. [PMID: 25743216].
[20]
Alam, S.; Khan, F. QSAR, docking, ADMET, and system pharmacology studies on tormentic acid derivatives for anticancer activity. J. Biomol. Struct. Dyn., 2018, 36(9), 2373-2390. [http://dx.doi.org/10.1080/07391102.2017.1355846]. [PMID: 28705120].
[21]
Mosmann, 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].
[22]
Orme, I.; Tuberculosis Drug Screening, P. Search for new drugs for treatment of tuberculosis. Antimicrob. Agents Chemother., 2001, 45(7), 1943-1946. [http://dx.doi.org/10.1128/AAC.45.7.1943-1946.2001]. [PMID: 11408205].

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