1,2,4,5-Tetraoxanes As New Chemical Entities With High Efficacy Against Malaria: Recent Advances In Drug Development
Keywords:
Malaria, 1,2,4,5-tetraoxanes, Drug resistance, Antimalarial agents, Reactive oxygen species (ROS)Abstract
Malaria continues to pose a significant global health threat, with approximately 239 million cases and around 409,000 deaths reported in 2023, predominantly among young children in sub-Saharan Africa. The emergence of drug-resistant strains of Plasmodium necessitates the urgent development of new therapeutic agents. This review focuses on the recent advancements in the synthesis, mechanisms of action, and evaluations of 1,2,4,5-tetraoxanes, a promising new class of antimalarial agents. 1,2,4,5-tetraoxanes exhibit unique mechanisms of action, including the generation of reactive oxygen species (ROS) and the inhibition of heme detoxification, which are crucial for the survival of Plasmodium parasites. Their ability to induce oxidative stress and disrupt vital metabolic processes positions them as strong candidates for combating malaria, particularly in light of the limitations of existing treatments such as artemisinin-based combination therapies (ACTs). The review also highlights the historical context of tetraoxane development, detailing various synthetic methodologies, including traditional approaches and modern techniques such as microwave-assisted synthesis and metal-catalyzed reactions. These advancements not only improve yield and efficiency but also facilitate the exploration of diverse tetraoxane derivatives. As malaria remains a pressing health issue, continued research into 1,2,4,5-tetraoxanes is essential for overcoming challenges related to drug resistance and enhancing treatment outcomes for affected populations.
References
N. F. Walker, B. Nadjm, and C. J. M. Whitty, "Malaria," Medicine, vol. 42, no. 2, pp. 100-106, 2014.
V. Soulard, H. Bosson-Vanga, A. Lorthiois, et al., "Plasmodium falciparum full life cycle and plasmodium ovale liver stages in humanized mice," Nat Commun., vol. 6, no. 1, p. 7690, 2015.
E. A. Ashley, A. Pyae Phyo, and C. J. Woodrow, "Malaria," Lancet, vol. 391, no. 10130, pp. 1608-1621, 2018.
J. Talapko, I. Škrlec, T. Alebić, M. Jukić, and A. Včev, "Malaria: the past and the present," Microorganisms, vol. 7, no. 6, p. 179, 2019.
R. N. Price, R. J. Commons, K. E. Battle, K. Thriemer, and K. Mendis, "Plasmodium vivax in the era of the shrinking P. falciparum map," Trends Parasitol., vol. 36, no. 6, pp. 560-570, 2020.
H. L. Qin, Z. W. Zhang, R. Lekkala, H. Alsulami, and K. P. Rakesh, "Chalcone hybrids as privileged scaffolds in antimalarial drug discovery: a key review," Eur J Med Chem., vol. 193, p. 112215, 2020.
J. Straimer, N. F. Gnädig, B. Witkowski, et al., "K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates," Science, vol. 347, no. 6220, pp. 428-431, 2015.
P. M. O'Neill, R. K. Amewu, S. A. Charman, et al., "A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance," Nat Commun., vol. 8, no. 1, p. 15159, 2017.
G. L. Ellis, R. Amewu, S. Sabbani, et al., "Two-step synthesis of achiral dispiro-1,2,4,5-tetraoxanes with outstanding antimalarial activity, low toxicity, and high-stability profiles," J Med Chem., vol. 51, no. 7, pp. 2170-2177, 2008.
Y. Tang, Y. Dong, and J. L. Vennerstrom, "Synthetic peroxides as antimalarials," Med Res Rev., vol. 24, no. 4, pp. 425-448, 2004.
L. I. L. Cabral, S. Pomel, S. Cojean, P. S. M. Amado, P. M. Loiseau, and M. L. S. Cristiano, "Synthesis and antileishmanial activity of 1,2,4,5-tetraoxanes against Leishmania donovani," Molecules, vol. 25, no. 3, p. 465, 2020.
D. Opsenica, G. Pocsfalvi, Z. Juranić, et al., "Cholic acid derivatives as 1,2,4,5-tetraoxane carriers: structure and antimalarial and antiproliferative activity," J Med Chem., vol. 43, no. 17, pp. 3274-3282, 2000.
R. S. Ramos, R. S. Borges, J. S. N. de Souza, I. F. Araujo, M. H. Chaves, and C. B. R. Santos, "Identification of potential antiviral inhibitors from hydroxychloroquine and 1,2,4,5-tetraoxanes analogues and investigation of the mechanism of action in SARS-CoV-2," Int J Mol Sci., vol. 23, no. 3, p. 1781, 2022.
B. A. Šolaja, N. Terzić, G. Pocsfalvi, et al., "Mixed steroidal 1,2,4,5-tetraoxanes: antimalarial and antimycobacterial activity," J Med Chem., vol. 45, no. 16, pp. 3331-3336, 2002.
J. L. Vennerstrom, H. N. Fu, W. Y. Ellis, et al., "Dispiro-1,2,4,5-tetraoxanes: a new class of antimalarial peroxides," J Med Chem., vol. 35, no. 16, pp. 3023-3027, 1992.
J. L. Vennerstrom, H. N. Fu, W. Y. Ellis, et al., "Dispiro-1,2,4,5-tetraoxanes: a new class of antimalarial peroxides," J Med Chem., vol. 35, no. 16, pp. 3023-3027, 2002.
Y. Dong, H. Matile, J. Chollet, R. Kaminsky, J. K. Wood, and J. L. Vennerstrom, "Synthesis and antimalarial activity of 11 dispiro-1,2,4,5-tetraoxane analogues of WR 148999. 7,8,15,16-Tetraoxadispiro[5.2.5.2]hexadecanes substituted at the 1 and 10 positions with unsaturated and polar functional groups," J Med Chem., vol. 42, no. 8, pp. 1477-1480, 1999.
J. L. Vennerstrom, Y. Dong, S. L. Andersen, et al., "Synthesis and antimalarial activity of sixteen dispiro-1,2,4,5-tetraoxanes: alkyl-substituted 7,8,15,16-tetraoxadispiro[5.2.5.2]hexadecanes," J Med Chem., vol. 43, no. 14, pp. 2753-2758, 2000.
K. J. Cheesman, S. J. McNamara, S. A. Lelièvre, et al., "Mixed tetraoxanes as efficient in vitro antimalarial agents with excellent selectivity against human cells," J Med Chem., vol. 52, no. 4, pp. 1837-1841, 2009.
T. Nogueira, A. N. Catto, J. L. Vennerstrom, J. Méndez, and M. M. Comini, "Dispiro-1,2,4,5-tetraoxanes selectively kill Leishmania infantum intracellular amastigotes and reveal promising activity in a mouse model of visceral leishmaniasis," Antimicrob Agents Chemother., vol. 66, no. 1, p. e01594-21, 2021.
H. J. Clark, J. G. Cannon, S. J. Bennett, et al., "Hybrids and spiro[piperidine‐4,3′‐tetraoxanes]," Helv. Chim. Acta, vol. 95, no. 7, pp. 1181-1197, 2012.
P. M. O'Neill, S. Sabbani, G. L. Nixon, et al., "Optimisation of the synthesis of second generation 1,2,4,5 tetraoxane antimalarials," Tetrahedron, vol. 72, no. 40, pp. 6118-6126, 2016.
C. M. Woodley, G. L. Nixon, N. Basilico, et al., "Enantioselective synthesis and profiling of potent, nonlinear analogues of antimalarial tetraoxanes E209 and N205," ACS Med. Chem. Lett., vol. 12, no. 7, pp. 1077-1085, 2021.
P. Singh, C. Sharma, B. Sharma, et al., "N‐sulfonylpiperidinedispiro‐1,2,4,5‐tetraoxanes exhibit potent in vitro antiplasmodial activity and in vivo efficacy in mice infected with P. berghei ANKA," Eur. J. Med. Chem., vol. 244, p. 114774, 2022.
N. Kumar, S. I. Khan, H. Atheaya, R. Mamgain, and D. S. Rawat, "Synthesis and in vitro antimalarial activity of tetraoxane‐amine/amide conjugates," Eur. J. Med. Chem., vol. 46, no. 7, pp. 2816-2827, 2011.
D. Opsenica, J. Radivojevic, I. Matic, et al., "Tetraoxanes as inhibitors of apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii and anti‐cancer molecules," J. Serb. Chem. Soc., vol. 80, no. 11, pp. 1339-1359, 2015.
M. K. Kumawat, P. Parida, and D. Chetia, "Synthesis, antimalarial activity evaluation and docking studies of some novel tetraoxaquines," Med. Chem. Res., vol. 25, no. 9, pp. 1993-2004, 2016.
S. Jansongsaeng, N. Srimongkolpithak, J. Pengon, S. Kamchonwongpaisan, and T. Khotavivattana, "5‐Phenoxy primaquine analogs and the tetraoxane hybrid as antimalarial agents," Molecules, vol. 26, no. 13, p. 3991, 2021.
Sharma, R. Sheyi, B. G. De La Torre, A. El‐Faham, and F. Albericio, "s‐Triazine: a privileged structure for drug discovery and bioconjugation," Molecules, vol. 26, no. 4, p. 864, 2021.
S. K. Awasthi, "Novel antimalarial dispiro‐1,2,4,5‐tetraoxanes and one pot method of synthesis thereof," U.S. Patent, April 13, 216AD.
K. Žmitek, S. Stavber, M. Zupan, et al., "Synthesis and antimalarial activities of novel 3,3,6,6‐tetraalkyl‐1,2,4,5‐tetraoxanes," Bioorg. Med. Chem., vol. 14, no. 23, pp. 7790-7795, 2006.
G. L. Ellis, R. Amewu, C. Hall, K. Rimmer, S. A. Ward, and P. M. O'Neill, "An efficient route into synthetically challenging bridged achiral 1,2,4,5‐tetraoxanes with antimalarial activity," Bioorg. Med. Chem. Lett., vol. 18, no. 5, pp. 1720-1724, 2008.
P. Coghi, I. A. Yaremenko, P. Prommana, et al., "Antimalarial and anticancer activity evaluation of bridged ozonides, aminoperoxides, and tetraoxanes," ChemMedChem, vol. 17, no. 20, p. e202200328, 2022.
V. Kumar et al., “Neuroprotective Effect of Boswellia serrata against 3-NP Induced Experimental Huntington’s Disease,” Current bioactive compounds, vol. 20, Jan. 2024, doi: https://doi.org/10.2174/0115734072272233231119161319.
P. Bhatt, V. Kumar, S. Singh, and Kunal Kanojia, “Climatic/Meteorological Conditions and Their Role in Biological Contamination,” pp. 56–88, Jun. 2024, doi: https://doi.org/10.1002/9781394178964.ch4.
Dharmendra Bhati et al., “FUSED AND SUBSTITUTED PYRIMIDINE DERIVATIVES AS POTENT ANTICANCER AGENTS,” Biochemical and Cellular Archives/Biochemical and cellular archives, vol. 24, no. 1, Jan. 2024, doi: https://doi.org/10.51470/bca.2024.24.1.749.
K. J. Mangala et al., “NANOCELLULOSE: A VERSATILE AND SUSTAINABLE CARRIER FOR DRUG AND BIOACTIVE COMPOUNDS,” Biochemical and Cellular Archives/Biochemical and cellular archives, vol. 24, no. 1, Jan. 2024, doi: https://doi.org/10.51470/bca.2024.24.1.553.
Rohit Kumar Trivedi et al., “REVOLUTIONIZING DRUG DELIVERY THROUGH 3D PRINTING TECHNOLOGY: CURRENT ADVANCES AND FUTURE DIRECTIONS,” Biochemical and Cellular Archives/Biochemical and cellular archives, vol. 24, no. 1, Jan. 2024, doi: https://doi.org/10.51470/bca.2024.24.1.521.
H. Rastogi, P. Bhatt, S. Garg, S. Kamboj, V. Deva, and R. Goel, “EXPLORING THE POTENTIAL OF QUANTUM DOTS AS LUMINOUS PROBES FOR TARGETED DRUG DELIVERY AND BIOIMAGING IN CLINICAL DIAGNOSTICS,” Biochemical and Cellular Archives/Biochemical and cellular archives, vol. 24, no. 1, Jan. 2024, doi: https://doi.org/10.51470/bca.2024.24.1.457.
M. shama, “CRISPR-Cas9 gene editing in pharmaceuticals : Current applications and future prospects,” Biochemical and Cellular Archives/Biochemical and cellular archives, vol. 23, no. S1, Dec. 2023, doi: https://doi.org/10.51470/bca.2023.23.s1.1655.
S. Arora, Saiphali, G. Dharmamoorthy Dharmendra Bhati, T. Gupta, and P. Bhatt, “Advancements in peptide-based therapeutics: Design, synthesis and clinical applications,” Biochemical and Cellular Archives/Biochemical and cellular archives, vol. 23, no. S1, Dec. 2023, doi: https://doi.org/10.51470/bca.2023.23.s1.1415.
M. Singhal et al., "Formulation development and characterization of powder for oral suspension containing H2 blocker drug to combat GERD and peptic ulcer," NeuroQuantology, vol. 20, no. 11, pp. 1258, 2022.
S. Ahamed, P. Bhatt, S. J. Sultanuddin, R. Walia, M. A. Haque, and S. B. InayathAhamed, "An Intelligent IoT enabled Health Care Surveillance using Machine Learning," in 2022 International Conference on Advances in Computing, Communication and Applied Informatics (ACCAI). IEEE, 2022.
V. Ahmed, S. Sharma, and P. Bhatt, "Formulation and evaluation of sustained release tablet of diltiazem hydrochloride," International Journal of Pharmaceutical Sciences and Research, vol. 11, no. 5, pp. 2193–2198, 2020.
A. E. Al-Snafi, S. Singh, P. Bhatt, and V. Kumar, "A review on prescription and non-prescription appetite suppressants and evidence-based method to treat overweight and obesity," GSC biol pharm sci, vol. 19, no. 3, pp. 148–155, 2022.
B. Baskar, S. Ramakrishna, and A. Daniela La Rosa, Eds., Encyclopedia of green materials. Singapore: Springer Nature Singapore, 2022.
P. Bhatt et al., "Nanorobots recent and future advances in cancer or dentistry therapy- A review," Am J PharmTech Res, vol. 9, no. 3, pp. 321–331, 2019.
P. Bhatt et al., "Citrus Flavonoids: Recent Advances and Future Perspectives On Preventing Cardiovascular Diseases," in The Flavonoids, 2024, pp. 131-152.
P. Bhatt et al., "Functional and tableting properties of alkali-isolated and phosphorylated barnyard millet (Echinochloa esculenta) starch," ACS Omega, vol. 8, no. 33, pp. 30294–305, 2023.
P. Bhatt et al., "Plasma modification techniques for natural polymer-based drug delivery systems," Pharmaceutics, vol. 15, no. 8, p. 2066, 2023.
P. Bhatt et al., "Comparative study and in vitro evaluation of sustained release marketed formulation of aceclofenac sustained release tablets," Pharma Science Monitor, vol. 9, no. 2, 2018.
P. Bhatt et al., "Development and characterization of fast dissolving buccal strip of frovatriptan succinate monohydrate for buccal delivery," Int J Pharm Investig, vol. 11, no. 1, pp. 69–75, 2021.
P. Bhatt et al., "Artificial intelligence in pharmaceutical industry: Revolutionizing drug development and delivery," The Chinese Journal of Artificial Intelligence, 2023.
P. Bhatt et al., "Blockchain technology applications for improving quality of electronic healthcare system," in Blockchain for Healthcare Systems, 2021, pp. 97–113.
P. Bhatt, "Mouth Dissolving Tablets Challenges, Preparation Strategies with a Special Emphasis on Losartan Potassium–A Review," World J. Pharm. Pharm. Sci, vol. 7, no. 9, pp. 271-287, 2018.
C. Goyal et al., "Estimation of shelf-life of Balachaturbhadrika syrup containing different sweetening agents," Res J Pharm Technol, pp. 5078–5083, 2022.
T. Kaur and S. Singh, "Controlled release of bi-layered malvidin tablets using 3D printing techniques," J Pharm Res Int, pp. 70–78, 2021.
M. Kaurav et al., "In-depth analysis of the chemical composition, pharmacological effects, pharmacokinetics, and patent history of mangiferin," Phytomed Plus, vol. 3, no. 2, p. 100445, 2023.
A. Kumar, P. Bhatt, and N. Mishra, "Irritable bowel Syndrome with reference of Alosetron Hydrochloride and Excipient profile used in the manufacturing of Alosetron tablet-A review," J Chem Pharm Sci, vol. 12, no. 03, pp. 71–78, 2019.
M. K. Malik et al., "Significance of chemically derivatized starch as drug carrier in developing novel drug delivery devices," Nat Prod J, 2022.
M. K. Malik et al., "Preclinical safety assessment of chemically cross-linked modified mandua starch: Acute and sub-acute oral toxicity studies in Swiss albino mice," ACS Omega, vol. 7, no. 40, pp. 35506–35514, 2022.
M. K. Malik et al., "Phosphorylation of alkali extracted mandua starch by STPP/STMP for improving digestion resistibility," ACS Omega, vol. 8, no. 13, pp. 11750–11767, 2023.
Pankaj, "Anti-cancer cyclodextrin nanocapsules based formulation development for lung chemotherapy," J Pharm Res Int, pp. 54–63, 2021.
Pankaj, "Cyclodextrin modified block polymer for oral chemotherapy," J Pharm Res Int, pp. 21–29, 2021.
V. Raghuwanshi et al., "Recent Advances In Nanotechnology For Combating Against Corona Virus Infection," Journal of Pharmaceutical Negative Results, pp. 1811-1820, 2022.
K. K. Sahu et al., "Utility of nanomaterials in wound management," in Nanotechnological Aspects for Next-Generation Wound Management, 2024, pp. 101–130.
S. K. Sharma et al., "Combined therapy with ivermectin and doxycycline can effectively alleviate the cytokine storm of COVID-19 infection amid vaccination drive: A narrative review," J Infect Public Health, vol. 15, no. 5, pp. 566–572, 2022.
S. K. Sharma and P. Bhatt, "Controlled release of bi-layered EGCG tablets using 3D printing techniques," J Pharm Res Int, pp. 5–13, 2021.
S. K. Sharma and S. Singh, "Antimicrobial Herbal Soap Formulation," Journal of Pharmaceutical Research International, vol. 32, no. 36, pp. 82-88, 2022.
S. Singh et al., "Cardiovascular comorbidity of COVID-19 disease: A review," WJPMR, vol. 8, no. 4, pp. 216–225, 2022.
S. Singh et al., "Phytonutrients, Anthocyanidins, and Anthocyanins: Dietary and Medicinal Pigments with Possible Health Benefits," in Advances in Flavonoids for Human Health and Prevention of Diseases, 2024, pp. 23-46.
S. Singh et al., "Digital Transformation in Healthcare: Innovation and Technologies," in Blockchain for Healthcare Systems, 2021, pp. 61–79.
S. Singh et al., "Alginate based Nanoparticles and Its Application in Drug Delivery Systems," Journal of Pharmaceutical Negative Results, pp. 1463-1469, 2022.
R. Johari et al., "Artificial Intelligence and Machine Learning in Drug Discovery and Development," in 2023 12th International Conference on System Modeling & Advancement in Research Trends (SMART), 2023, pp. 556-561.
P. Bhatt et al., “Impact of Cross‐Linking on the Physicochemical and Physiological Characteristics of Barnyard Millet (Echinochloa frumentacea) Grains Starch,” Stärke/Starch, May 2024, doi: https://doi.org/10.1002/star.202300285.
V. Kumar et al., “Ultrasound assisted techniques for starch modification to develop novel drug delivery systems: A comprehensive study,” Journal of bioactive and compatible polymers, May 2024, doi: https://doi.org/10.1177/08839115241249143.
H. Pates and C. Curtis, "Mosquito behavior and vector control," Annu Rev Entomol., vol. 50, pp. 53-70, 2005.
World Health Organization, World Malaria Report 2021, World Health Organization, 2021, p. 322.
O. P. S. Patel, R. M. Beteck, and L. J. Legoabe, "Exploration of artemisinin derivatives and synthetic peroxides in antimalarial drug discovery research," Eur J Med Chem., vol. 213, p. 113193, 2021.
R. Tripathi, C. W. Jefford, and G. P. Dutta, "Blood schizontocidal activity of selected 1,2,4-trioxanes (Fenozans) against the multidrug-resistant strain of Plasmodium yoelii nigeriensis (MDR) in vivo," Parasitology, vol. 133, no. 1, pp. 1-9, 2006
M. S. Tucker, T. Mutka, K. Sparks, J. Patel, and D. E. Kyle, "Phenotypic and genotypic analysis of in vitro-selected artemisinin-resistant progeny of Plasmodium falciparum," Antimicrob Agents Chemother., vol. 56, no. 1, pp. 302-314, 2012.
S. Chakraborty, B. Alam, and S. Biswas, "New insights of falcipain 2 structure from Plasmodium falciparum 3D7 strain," Biochem Biophys Res Commun., vol. 590, pp. 145-151, 2022.
K. A. Moser, E. F. Drábek, A. Dwivedi, et al., "Strains used in whole organism Plasmodium falciparum vaccine trials differ in genome structure, sequence, and immunogenic potential," Genome Med., vol. 12, no. 1, p. 6, 2020.
D. A. Van Schalkwyk, R. Burrow, G. Henriques, et al., "Culture-adapted Plasmodium falciparum isolates from UK travellers: in vitro drug sensitivity, clonality and drug resistance markers," Malar J., vol. 12, no. 1, p. 320, 2013.