Tuberculosis is a deadly, contagious disease caused by the bacterium Mycobacterium tuberculosis. The emergence of multidrug-resistant tuberculosis strains has made the treatment of the disease challenging. Therefore, developing potent antitubercular compounds that can overcome drug resistance with low side effects is an urgent need. Piperazine is a cyclic structure composed of two methylene groups linked by two nitrogen atoms. In drugs approved by the FDA, the piperazine structure is one of the most commonly used heterocyclic rings. Piperazine and its derivatives are found in the structure of many compounds with various pharmacological effects. Rifampicin, ciprofloxacin, and ofloxacin are some antitubercular drugs that contain a piperazine structure. This review explores recent research on piperazine-based drugs for tuberculosis treatment and aims to foster the development of innovative antitubercular agents.
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Antitüberküler Bileşiklerde Piperazin Yapısı
Year 2024,
Volume: 44 Issue: 3, 275 - 288, 01.09.2024
Tüberküloz, Mycobacterium tuberculosis basilinin sebep olduğu öldürücü, bulaşıcı bir hastalıktır. Çoklu ilaca dirençli tüberküloz suşlarının ortaya çıkması hastalığın tedavisini zorlaştırmıştır. Bu nedenle ilaç direncinin üstesinden gelebilecek ve düşük yan etkili güçlü antitüberküler bileşiklerin geliştirilmesi acil bir ihtiyaçtır. Piperazin, iki adet azot atomu ile birbirine bağlı iki metilen grubundan oluşan bir siklik yapıdır. FDA tarafından onaylanan ilaçlarda piperazin yapısı en çok kullanılan heterosiklik halkalardan biridir. Piperazin ve türevleri, çeşitli farmakolojik etkilere sahip birçok bileşiğin yapısında yer almaktadır. Rifampisin, siprofloksasin ve ofloksasin yapısında piperazin taşıyan antitüberküler ilaçlardan bazılarıdır. Bu derleme, piperazin içeren antitüberküler ilaçlar üzerinde yapılan son araştırmaları gözden geçirmekte ve yenilikçi antitüberküler bileşiklerin tasarımına yardımcı olmayı amaçlamaktadır.
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(2023). https://wwwwhoint/teams/global-tuberculosisprogramme/
tb-reports/global-tuberculosis-report-2023. 2023
2. Somoskovi A, Dormandy J, Parsons LM, Kaswa M, Goh KS,
Rastogi N, et al. Sequencing of the pncA gene in members of
the Mycobacterium tuberculosis complex has important diagnostic
applications: Identification of a species-specific pncA
mutation in “Mycobacterium canettii” and the reliable and
rapid predictor of pyrazinamide resistance. J Clin Microbiol.
2007;45(2):595-9. https://doi.org/10.1128/jcm.01454-06
3. Schaller MA, Wicke F, Foerch C, Weidauer S. Central Nervous
System Tuberculosis. Clin Neuroradiol. 2019;29(1):3-18.
https://doi.org/10.1007/s00062-018-0726-9
4. Alsayed SSR, Lun S, Payne A, Bishai WR, Gunosewoyo H.
Facile synthesis and antimycobacterial activity of isoniazid,
pyrazinamide and ciprofloxacin derivatives. Chem Biol Drug
Des. 2021;97(6):1137-50. https://doi.org/10.1111/cbdd.13836
5. Singh V, Pacitto A, Donini S, Ferraris DM, Boros S, Illyes
E, et al. Synthesis and Structure-Activity relationship
of 1-(5-isoquinolinesulfonyl)piperazine analogues as inhibitors
of Mycobacterium tuberculosis IMPDH. Eur J
Med Chem. 2019;174:309-29. https://doi.org/10.1016/j.ejmech.
2019.04.027
6. Patel VR, Park Won S. An Evolving Role of Piperazine Moieties
in Drug Design and Discovery. Mini-Rev Med Chem.
2013;13(11):1579-601. http://dx.doi.org/10.2174/1389557511
3139990073
7. Shaquiquzzaman M, Verma G, Marella A, Akhter M, Akhtar
W, Khan MF, et al. Piperazine scaffold: A remarkable
tool in generation of diverse pharmacological agents. Eur J
Med Chem. 2015;102:487-529. https://doi.org/10.1016/j.ejmech.
2015.07.026
8. Vitaku E, Smith DT, Njardarson JT. Analysis of the Structural
Diversity, Substitution Patterns, and Frequency of Nitrogen
Heterocycles among U.S. FDA Approved Pharmaceuticals. J
Med Chem. 2014;57(24):10257-74. https://doi.org/10.1021/
jm501100b
9. Romanelli MN, Braconi L, Gabellini A, Manetti D, Marotta
G, Teodori E. Synthetic Approaches to Piperazine-Containing
Drugs Approved by FDA in the Period of 2011–2023. Molecules
[Internet]. 2024; 29(1). Available from: https://doi.
org/10.3390/molecules29010068.
10. Zhang R-H, Guo H-Y, Deng H, Li J, Quan Z-S. Piperazine
skeleton in the structural modification of natural products:
a review. J Enzyme Inhib Med Chem. 2021;36(1):1165-97.
https://doi.org/10.1080/14756366.2021.1931861
11. Rachelson MH, Ferguson WR. Piperazine in the treatment
of enterobiasis. AMA Am J Dis Child. 1955;89(3):346-9.
doi:10.1001/archpedi.1955.02050110412013
12. Fang Z, Zhang B, Xing W, Yu H, Xing C, Gong N, et al.
An Evolving Role of Aqueous Piperazine to Improve the
Solubility of Non-Steroidal Anti-Inflammatory Drugs. J
Pharm Sci. 2022;111(10):2839-47. https://doi.org/10.1016/j.
xphs.2022.05.009
13. Girase PS, Dhawan S, Kumar V, Shinde SR, Palkar MB, Karpoormath
R. An appraisal of anti-mycobacterial activity with
structure-activity relationship of piperazine and its analogues:
A review. Eur J Med Chem. 2021;210:112967. https://doi.
org/10.1016/j.ejmech.2020.112967
14. Evranos-Aksöz B. New drug candidates in tuberculosis
treatment. Türk Hijyen ve Deneysel Biyoloji Dergisi.
2014;71:207-16. https://doi.org/10.5505/TurkHijyen.
2014.35492
15. O’Brien RJ, Spigelman M. New Drugs for Tuberculosis: Current
Status and Future Prospects. Clin Chest Med. 2005;26(2):327-
40. https://doi.org/10.1016/j.ccm.2005.02.013
16. Biltekin N, Ülger M. Tüberküloz tedavisinde kullanılan antitüberküloz
ilaçlar Antituberculosis drugs used in the treatment
of tuberculosis. Mersin Üniversitesi Sağlık Bilimleri Dergisi.
2023;3:525-42. https://doi.org/10.26559/mersinsbd.1213832
17. Maruri F, Sterling TR, Kaiga AW, Blackman A, van der Heijden
YF, Mayer C, et al. A systematic review of gyrase mutations
associated with fluoroquinolone-resistant Mycobacterium
tuberculosis and a proposed gyrase numbering system.
J Antimicrob Chemother. 2012;67(4):819-31. https://doi.
org/10.1093/jac/dkr566
18. Zhanel GG, Walkty A, Vercaigne L, Karlowsky JA, Embil
J, Gin AS, et al. The new fluoroquinolones: A critical
review. Can J Infect Dis. 1999;10(3):207-38. https://doi.
org/10.1155/1999/378394
19. Sood R, Rao M, Singhal S, Rattan A. Activity of RBx 7644
and RBx 8700, new investigational oxazolidinones, against
Mycobacterium tuberculosis infected murine macrophages.
Int J Antimicrob Agents. 2005;25(6):464-8. https://doi.
org/10.1016/j.ijantimicag.2005.01.021
20. Emanuele P, Mario CR, Giovanni Battista M. Regimens to treat
multidrug-resistant tuberculosis: past, present and future perspectives.
European Respiratory Review. 2019;28(152):190035.
https://doi.org/10.1183/16000617.0035-2019
21. Kilbile JT, Tamboli Y, Gadekar SS, Islam I, Supuran CT, Sapkal
SB. An insight into the biological activity and structurebased
drug design attributes of sulfonylpiperazine derivatives.
J Mol Struct. 2023;1278:134971. https://doi.org/10.1016/j.
molstruc.2023.134971
22. Rizwan M, Noreen S, Asim S, Liaqat Z, Shaheen M, Ibrahim
H. A comprehensive review on the synthesis of substituted
piperazine and its novel bio-medicinal applications. Chemistry
of Inorganic Materials. 2024;2:100041. https://doi.
org/10.1016/j.cinorg.2024.100041
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