Bedaquiline is a new drug approved to treat multidrug-resistant tuberculosis (MDR-TB). However, it has some challenges including cardiotoxicity and hepatotoxicity likely due to its highly lipophilic structure. Researchers have worked to develop analogues of bedaquiline with reduced lipophilicity to minimize these toxicities. One study developed a 6-cyano analogue that showed significantly decreased lipophilicity while maintaining similar antibacterial activity. Other studies substituted the naphthalene unit of bedaquiline's structure with different heterocycles. Optimizing the balance of lipophilicity, basicity, and other structural properties may help address the toxicity issues and make bedaquiline a better treatment for MDR-

1. WELCOME

2. Review: A Structural Insight of Bedaquiline for the
Cardiotoxicity and Hepatotoxicity
Presented By: Tahmina Khan
M. Pharm. First Year
Pharmaceutical Chemistry
Department of Pharmaceutical Sciences Rashtrasant Tukadoji
Maharaj Nagpur University, Nagpur - 440 033

4. CONTENT
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 Introduction
 Challenges with bedaquiline
 Structural features of bedaquiline responsible for the activity and toxicity
 Recently reported less lipophilic bedaquiline analogue with minimal cardio-
toxicity
 Discussion and future perspectives
 References

5.  Tuberculosis (TB) is an airborne bacterial disease.
 The WHO estimates that 1.8 billion people are infected with Mycobacterium
tuberculosis (M. tb).
 Mycobacterium tuberculosis is a fairly large nonmotile, rod-shaped bacterium.
 Highly Survivable because of :
 Resistance to antibiotics.
 Protection from oxygen free radicals.
 Grow intracellularly within macrophages.
5
fig. 1.Tuberculosis
Tuberculosis

6.  TB infectious is treated by DOTS but this method could be:
 Ineffective and develop resistance toward anti-TB.
 Multidrug-resistant TB (MDR-TB)
 Extensive drug-resistant TB (XDR-TB)
 The drug-resistant to treat this disease is still the primary issue of why the
number of deaths and lethality is hard to combat. Therefore, the discovery
and development of new effective anti TB drugs are extremely needed.
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7.  Bedaquiline has recently come out as a new drug to treat MDR-TB.
 The IC50 value of bedaquiline was reported to be remarkably low, effectively
inhibiting mycobacterial ATP synthase. In addition, the mode of action of
bedaquiline is highly target-specific.
7
Fig no. 2. Structure of bedaquline

8.  In addition to the standard MDR-TB therapy, Bedaquiline shows faster
bactericidal activity.
 It is very lipophilic, however, and probably contributes to its long terminal half-
life of 5–6 months.
 Bedaquiline shows inhibition of the cardiac potassium channel hERG (human
Ether-à-go-Related Gene; KCNH2) with the concomitant risk of delayed
ventricular repolarization (QT interval).
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Challenges With Bedaquiline

9. 9
Fig. 3. Challenges associated with bedaquiline

10. 1. Guillemont et al., the pioneer researcher group and inventor of bedaquiline
reported the interesting structural activity relationship studies leading to the
discovery of TMC207 and features of Diaryl Quinol in 2011.
2. Fox et al., reported recently that N-monodesmethyl metabolite (M2) of
Bedaquiline is more toxic and less bactericidal.
 i.e The primary metabolite of bedaquiline, M2, is removed mainly in the stool,
with only 1–4% removed in the urine.
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Structural Features of Bedaquiline Responsible for the Activity
and toxicity

11. 11
Fig. 4. Structural feature responsible for the activity of bedaquiline

12. 12
Fig. 5. Structural feature responsible for the toxicity of bedaquiline

13.  Several attempts were made by the different Researcher to optimize the
Bedaquiline to have minimal lipophilicity and cardio-toxicity. The details of which
are discussed below:
1. Sutherland et al., synthesized the modified derivatives of bedaquiline, where they
replaced the naphthalene unit with a range of widely differing lipophilic bicycle
heterocycles.
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Recently Reported Less Lipophilic Bedaquiline Analogue With
Minimal Cardio-toxicity.

14. 14
Fig. 6. Naphthalene substituted analogue of bedaquiline

15. 15
Fig. 7. 6-cyano substituted analogue of bedaquiline
2. Tong et al., Synthesized the 6-cyano (compound 7) analogue of the bedaquiline
and reported the significant decrease in lipophilicity (clogp = 4.64) with just
humble impacts on MIC90 (0.09 μg/ml) values as responsible for high lipid
solubility and cardiotoxicity of bedaquiline.

16. 3. Fernandez et al., Reported that the basic amine functional group present in
bedaquiline, which is predominantly protonated at shown in fig 07.
4. Tong et al., synthesized the 6-cyano (Compound 7) analouge of the bedaquiline and
reported the significant decrease in lipophilicity (clogP = 4.64) with just humble
impacts on MIC (0.09 μg/ml) values as shown in Fig 07.
5. Choi et al., Synthesized and evaluated bedaquiline analogs, in which the phenyl unit
was substituted by monocyclic lipophilic heterocycles (thiophenes, furans, pyridines)
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17.  It could be deduced from the literature review that the appropriate balance of lipid
solubility and basicity of the terminal dimethylamino group could solve
hepatotoxicity and cardiotoxicity problems associated with Bedaquiline and make it
an appropriate candidate for treatment of MDR – TB.
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Discussion And Future Perspectives
Fig. 8(A). Activity-toxicity optimization of Bedaquiline

18. 18
Fig. 8(B). Activity-toxicity optimization of Bedaquiline

19. 1. WHO. Global control tuberculosis. www.who.int/tb/publications/global_ report/
2010/gtbr10.pdf; 2010.
2. WHO. Stop TB partnership. www.WHO.int/tb/publications/2009/fact sheet_tb_
2009update_dec2009.pdf; 2009.
3. Udwadia ZF, Amale RA, Ajbani KK, et al. Totally drug-resistant tuberculosis in India. Clin
Infect Dis 2012;54(4):579–81.
4. Svensson EM, Murray S, et al. Rifampicin and rifapentine significantly reduce
concentrations of bedaquiline, a new anti-TB drug. J Antimicrob Chemother
2014;70(4):1106–11014.
5. Andries K, Verhasselt P, et al. A diarylquinoline drug active on the ATP synthase of
Mycobacterium tuberculosis. Science 2005;307(5707):223–7.
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References

20. 6. Huitric E, Verhasselt P, et al. In vitro antimycobacterial spectrum of a diarylquinoline ATP
synthase inhibitor. Antimicrob Agents Chemother 2007;51(11):4202–4
7. Fox GJ, Menzies D. A review of the evidence for using bedaquiline (TMC207) to treat
multi-drug resistant tuberculosis. Infect Dis Ther 2013;2(2):123–44.
8. Sutherland HS, Tong AS, et al. Structure-activity relationships for analogs of the
tuberculosis drug bedaquiline with the naphthalene unit replaced by bicyclic heterocycles.
Bioorg Med Chem 2018;26(8):1797-809.
9. Tong AS, Choi PJ, et al. 6-Cyano analogues of bedaquiline as less lipophilic and
potentially safer diarylquinolines for tuberculosis. ACS Med Chem Lett 2017;8(10):1019–
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THANK YOU