30DEC

Libyan International Conference for Health Sciences

The First Libyan International Conference for Health Sciences (2024): Open University, Tripoli, Libya
Mediterranean Journal of Pharmacy and Pharmaceutical Sciences
https://app.periodikos.com.br/journal/medjpps/article/doi/10.5281/zenodo.10208022

Mediterranean Journal of Pharmacy and Pharmaceutical Sciences

review

A progressive review on the synthesis of Atovaquone (an anti-malarial drug), empowered by the critical examination of prior-art disclosures

Sanjay Sukumar Saralaya, Shridhara Kanakamajalu

Downloads: 1
Views: 357

Abstract

In this article, a systematic flow of contents was provided about the synthesis of Atovaquone 1a on a critical examination of the prior arts. Several patents and study articles were published, disclosing different synthetic methods for the preparation of Atovaquone 1a at various scales. Based on the starting materials used, there are a few one-step, two-step and multi-step synthetic routes were reported with varied yields. In this work, we have put in our sincere effort to collect all the synthetic routes of Atovaquone 1a in detail with distinct and elaborate reaction schemes for better and collective process clarity. From this review, global researchers will get a platform to re-design or re-work the synthetic approach of Atovaquone 1a with better atom economy and purity. In addition, the drug commercialization angle could also be looked at during the design stage itself alongside green chemistry concepts. We have done a chronic analysis of study articles to highlight the commercial feasibility of the disclosed synthetic methods. A special emphasis was given to the synthetic routes with process development initiatives towards, recovery/reuse of costly starting materials/ reagents/solvents and their feasibility for large-scale manufacturing of drug Atovaquone 1a.

Keywords

Atovaquone, coupling, epimerization, hydrolysis, recrystallization, synthesis

References

  1. Hughes WT (1995) The role of atovaquone tablets in treating pneumocystis carinii pneumonia. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology. 8 (3): 247-252. doi: 10.1097/00042560-199503010-00005
  2. McKeage K, Scott L (2003) Atovaquone/proguanil: a review of its use for the prophylaxis of Plasmodium falciparum malaria. Drugs. 63 (6): 597-623. doi: 10.2165/00003495-200363060-00006
  3. Shanks GD, Gordon DM, Klotz FW, Aleman GM, Oloo AJ, Sadie D, Scott TR (1998) Efficacy and safety of atovaquone/proguanil as suppressive prophylaxis for Plasmodium falciparum malaria. Clinical Infectious Diseases. 27 (3): 494-499. doi: 10.1086/514710
  4. Sukwa TY, Mulenga M, Chisdaka N, Roskell NS, Scott TR (1999) A randomized, double-blind, placebo-controlled field trial to determine the efficacy and safety of Malarone (atovaquone/proguanil) for the prophylaxis of malaria in Zambia. The American Journal of Tropical Medicine and Hygiene. 60 (4): 521-525. doi: 10.4269/ajtmh. 1999.60.521
  5. Staines HM, Burrow R, Teo BHY, ChisSter I, Kremsner PG, Krishna S (2018) Clinical implications of Plasmodium resistance to atovaquone/proguanil: a systematic review and meta-analysis. The Journal of Antimicrobial Chemotherapy. 73 (3): 581-595. doi: 10.1093/jac/dkx431
  6. Xiang M, Kim H, Ho VT, Walker SR, Bar-Natan M, Anahtar M, Liu S, Toniolo PA, Kroll Y, Jones N, Giaccone ZT, Heppler LN, Ye DQ, Marineau JJ, Shaw D, Bradner JE, Blonquist T, Neuberg D, Hetz C, Frank DA (2016) Gene expression-based discovery of atovaquone as a STAT3 inhibitor and anticancer agent. Blood. 128 (14): 1845-1853. doi: 10.1182/blood-2015-07-660506
  7. Carter-Timofte ME, Arulanandam R, Kurmasheva N, Fu K, Laroche G, Taha Z, van der Horst D, Cassin L, van der Sluis RM, Palermo E, Di Carlo D, Jacobs D, Maznyi G, Azad T, Singaravelu R, Ren F, Hansen AL, Idorn M, Holm CK, Olagnier D (2021) Antiviral potential of the antimicrobial drug atovaquone against SARS-CoV-2 and emerging variants of concern. ACS Infectious Diseases. 7 (11): 3034-3051. doi.org/10.1021/acsinfecdis.1c00278
  8. Sykes JE, Papich MG (2014) Antiprotozoal Drugs. In: Canine and Feline Infectious Diseases, Elsevier, Saunders. 97-104. ISBN: 9780323241946.
  9. Krause PJ, Lepore T, Sikand VK, Gadbaw J, Jr Burke G, Telford SR, 3rd Brassard P, Pearl D, Azlanzadeh J, Christianson D, McGrath D, Spielman A (2000) Atovaquone and azithromycin for the treatment of babesiosis. The New England Journal of Medicine. 343 (20): 1454-1458. doi: 10.1056/NEJM 200011163432004
  10. Baggish AL, Hill DR (2002) Antiparasitic agent atovaquone. Antimicrobial Agents and Chemotherapy. 46 (5): 1163-1173. doi: 10.1128/AAC.46.5.1163-1173.2002
  11. Clark HL, Minns MS, Sun Y, de Jesus T, Ghannoum MG, Pearlman E (2018) Atovaquone impairs growth of Aspergillus and Fusarium keratitis isolates by modulating mitochondrial function and zinc homeostasis. Investigative Ophthalmology and Visual Science. 59 (3): 1589-1598. doi: 10.1167 /iovs.17-22585
  12. Futuro DO, Ferreira PG, Nicoletti CD, Borba-Santos LP, Silva FCDA, Rozental S, Ferreira VF (2018) The antifungal activity of naphthoquinones: An integrative review. Anais Da Academia Brasileira de Ciencias. 90 (1S 2): 1187-1214. doi: 10.1590/0001-3765201820170815
  13. Sanjay SS, Shashiprabha, Shridhara K, Nagarajan K (2022) Synthesis, structural elucidation and reaction optimization studies of a novel prodrug of Atovaquone. Journal of Chemical Sciences (Bangalore, India). 134 (1): 33. doi: 10.1007/s12039-022-02029-1
  14. Kasturi TR, Arunachalam T (1966) A general method of preparation of substituted 2-hydroxy-1.4-Quinones. Canadian Journal of Chemistry. 44 (9): 1086-1089. doi: 10.1139/v66-161
  15. Spyroudis S (2000) Hydroxyquinones: Synthesis and reactivity. Molecules (Basel, Switzerland). 5 (12): 1291-1330. doi: 10.3390/51201291
  16. Paengsri W, Promsawan N, Baramee A (2021) Synthesis and evaluation of 2-hydroxy-1,4-naphtho-quinone derivatives as potent antimalarial agents. Chemical and Pharmaceutical Bulletin. 69 (3): 253-257. doi: 10.1248/ cpb.c20-00770
  17. Hudson AT, Randall W (1991) Naphthoquinone derivatives, US Patent 5053432A, filed on December 26, 1989.
  18. Hudson AT, Latter V (1994) Medicaments, EP Patent 0580185 A1, filed on August 15, 1989.
  19. Coppa F, Fontana F, Lazzarini E, Minisci F (1992) A new selective method for the homolytic alkylation and carboxylation of quinones by monoesters of oxalic acid. Chemistry Letters. 21 (7): 1299-1302. doi: 10.1246/cl. 1992.1299
  20. Williams DR, Clark MP (1998) Synthesis of atovaquone. Tetrahedron Letters. 39 (42): 7629-7632. doi: 10.1016 /s0040-4039(98)01691-8
  21. Verma SS, Patel DJ, Dwivedi SD (2008) Process for preparation of Atovaquone and the conversion of cis-isomer to trans-isomer, WO Patent 2008122988 A1, filed on April 3, 2008.
  22. Wang Y, Liao J, Li Q, Liu Q (2008) Process for preparation of Atovaquone, CN Patent 101265171 A, filed on April 30, 2008. doi: Nil.
  23. Antonio N, Mara S, Annibale S, Stefan M (2010) Process for the preparation of trans-2,3-disubstituted naphthoquinones, US Patent 7842840 B2, filed on May 6, 2008.
  24. Zhu F, Qiao H, Bekhazi M (2010) Process for preparation of Atovaquone via coupling of 2-thioxopyridin-1(2H)-yl 4-(4-chlorophenyl)cyclohexane with 1,4-naphthoquinone, WO Patent 2010001379 A1, filed on June 30, 2008.
  25. Gui H, Zhou Q, Hu X (2010) A process for preparing Atovaquone from 4-(4-chlorophenyl)-cyclohexane-carboxylic acid and 2-chloro-1,4-naphthalenedione, CN Patent 101774901 A, filed on Jan 9, 2009.
  26. Saralaya SS, Shashikumar HS, Shashiprabha, Kanakamajalu S, Ranganathan KR, Veeraswamy A, Govindaraju J, Kothapalli SR, Nagarajan K (2012) Preparation of naphthoquinone compounds using 2,3-dihalonaphthoquinone, US Patent 8283499 B2, filed on March 6, 2009.
  27. Saralaya SS, Shashiprabha, Kanakamajalu S, Nagarajan K, Ranganathan KR (2022) A systematic study towards the synthesis, isolation, and recrystallization of atovaquone, an antimalarial drug: A sustainable synthetic pathway. Mapana Journal of Sciences. 21 (1): 19-37. doi: 10.12723/mjs.60.2
  28. Saralaya SS, Shashiprabha, Kanakamajalu S, Nagarajan K, Ranganathan KR (2022) A novel and sustainable method for the synthesis of 2-chloro-3-[trans-4-(4-chlorophenyl) cyclohexyl]-1,4-naphtho-quinone, accomplished by systematic process development studies - Trans-Cl synthesis, Mapana Journal of Sciences. 21 (3): 1-19. doi: 10.12723/mjs.62.0
  29. Kumar A, Singh D, Mathur P, Kore SS, Buchude VS (2010) A new process for preparation of Atovaquone and novel intermediates thereof, US Patent 7847127 B2, filed on October 21, 2009.
  30. Roy KBN, Singh GP, Lathi PS, Agrawal MK, Mitra R, Trivedi A (2012) A process for the preparation of Atovaquone, WO Patent 2012153162 A1, filed on June 28, 2011.
  31. Dwyer AN, Gordon A, Urquhart M (2012) Novel process for preparation of Atovaquone and intermediates thereof, WO Patent 2012080243 A2, filed on December 13, 2011.
  32. Vyas JR, Yadav RR, Bhimani AS (2013) Novel process for selective isolation and purification of 2-[4-(4-chlorophenyl) cyclohexyl-3-chloro-l, 4-naphthoquinone and Atovaquone, WO Patent 2013098832 A2, filed on September 7, 2012.
  33. Vyas JR, Yadav RR, Bhimani AS (2011) Novel purification method for 2-chloro-3-[4-(4-chlorophenyl) cyclohexyl]-1,4-naphthoquinone and Atovaquone, IN Patent 2011MU02505 A, filed on September 8, 2011.
  34. Parikh JR, Doering WVE (1967) Sulfur trioxide in the oxidation of alcohols by dimethyl sulfoxide. Journal of the American Chemical Society. 89 (21): 5505-5507. doi: 10.1021/ja00997a067
  35. Rylander PN (1967) Hydrogenation of aldehydes. In: Catalytic hydrogenation over platinum metals, Elsevier, Academic Press, pp. 238-257. ISBN: 9780323145862.
  36. Barcia JC, Cruces J, Estevez JC, Estevez RJ, Castedo L (2002) Palladiumcatalyzed synthesis of o‐acetylbenzoic acids: A new, efficient general route to 2hydroxy3-phenyl-1,4naphthoquinones and indolo [2,3b]naphthalene 6,11diones. ChemInform. 33 (42): 109-109. doi: 10.1002/chin.200242109
  37. Britton H, Catterick D, Dwyer AN, Gordon AH, Leach SG, McCormick C, Mountain CE, Simpson A, Stevens DR, Urquhart MWJ, Wade CE, Warren J, Wooster NF, Zilliox A (2012) Discovery and development of an efficient process to atovaquone. Organic Process Research and Development. 16 (10): 1607-1617. doi: 10.1021/ op300165q
  38. Iosub AV, Wallentin CJ, Bergman J (2018) Celebrating 100 years of the Rosenmund reaction. Nature Catalysis. 1 (9): 645-648. doi: 10.1038/s41929-018-0143-0
  39. Dong M, Yan B, Guo Q, Dong K, Peng X, Wu M (2014) Benzoquinone, its preparation and application for preparation of Atovaquone, CN Patent 103570520 A, filed on August 21, 2013.
  40. Zhu F, Bekhazi M (2011) Process for the epimerization of atovaquone isomer, atovaquone intermediates and mixture thereof, US Patent 0144347 A1, filed on June 30, 2008.
  41. Dike SY, Singh D, Thankachen BN, Sharma B, Mathur PK, Kore S, Kumar A (2014) A single-pot synthesis of atovaquone: An antiparasitic drug of choice. Organic Process Research and Development. 18 (5): 618-625. doi: 10.1021/op500032w
  42. Zhang J (2016) Process for the preparation of Atovaquone, CN Patent 105622381 A, filed on November 7, 2014.
  43. Cui Q, Wang B, Xu X, Wang Q, Ju L (2020) Method for preparing Atovaquone, CN Patent 110734369 A, filed on July 19, 2018.
  44. Khan J, Rani A, Aslam M, Pandey G, Nand PB (2023) A review on the synthesis and application of naphthoquinone-based drugs. Results in Chemistry. 6 (101138): 101138. doi: 10.1016/j.rechem. 2023.101138

Submitted date:
11/12/2023

Reviewed date:
11/25/2023

Accepted date:
11/27/2023

Publication date:
11/26/2023

6563c38da953956dae4de753 medjpps Articles
Links & Downloads

Mediterr J Pharm Pharm Sci

Share this page
Page Sections