Journal of Natural Remedies

Open Access Open Access  Restricted Access Subscription Access

Deuterium - A Natural Isotope to Combat Microbial Resistance


Affiliations
1 Dr APJ Abdul Kalam Research Laboratory, Department of Pharmaceutical Chemistry, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur – 603203, Tamil Nadu, India
2 Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER) Hajipur District: Vaishali, Hajipur - 844102, Bihar, India
3 Faculty of Pharmacy, Karpagam Academy of Higher Education, Pollachi Main Road, Eachanari Post, Coimbatore - 641021, Tamil Nadu, India
4 Department of Pharmacognosy and Phytochemistry, Parul Institute of Pharmacy and Research, Parul University, Vadodara, Gujarat – 391760, India
 

Deuterated medicinal chemistry is an attempt to introduce deuterium into existing drug molecules through the replacement of hydrogen atoms (-H) with deuterium (-D). The process of deuteration is to reduce the rates of breaking the carbonhydrogen bond. If the carbon-hydrogen bond breaking is the rate-determining step in the biotransformation of the drug, the deuterated drug may show improved pharmacokinetic characteristics, such as a longer half-life, hence lowering the need for frequent dosing. In this review, we discuss the improvement in the drug’s pharmacokinetic profile with deuterium. Further, this Deuterium exchange chemistry can reduce toxicity and be safe for human use. Also, the drugs experimented with using deuterium are discussed as how deuterated chemistry can help fight antimicrobial resistance. Beyond all, still, the design and development of a successful deuterated drug with acceptable efficacy is hence a challenge. The translation of hypotheses from laboratory experiments to clinical application and further to real-time practice is unpredictable. Also, long-term drug stability and toxicity studies for individual drugs are to be studied which may vary from patient to patient.

Keywords

Antimicrobial Resistance, Deuterium, Metronidazole, Pharmacokinetic Property
Font Size

User

Notifications
JOURNAL COVERS
  

  • Urey HC, Brickwedde FG, Murphy GM. A hydrogen isotope of mass 2. Physical Review. 1932; 39(1):164. https://doi.org/10.1103/PhysRev.39.164

  • Harbeson SL, Tung RD. Deuterium in drug discovery and development. In Annual Reports in Medicinal Chemistry. Academic Press; 2011. p. 403-417. https://doi.org/10.1016/ B978-0-12-386009-5.00003-5

  • Pirali T, Serafini M, Cargnin S, Genazzani AA. Applications of deuterium in medicinal chemistry. Journal of Medicinal Chemistry. 2019; 62(11):5276-97. https://doi.org/10.1021/acs.jmedchem.8b01808 PMid:30640460

  • Bartell LS, Roth EA, Hollowell CD, Kuchitsu K, Young Jr JE. Electron‐diffraction study of the structures of C2H4 and C2D4. The Journal of Chemical Physics. 1965; 42(8):2683- 6. https://doi.org/10.1063/1.1703223

  • Nelson SD, Trager WF. The use of deuterium isotope effects to probe the active site properties, mechanism of cytochrome P450-catalyzed reactions, and mechanisms of metabolically dependent toxicity. Drug Metabolism and Disposition. 2003; 31(12):1481-97. https://doi.org/10.1124/dmd.31.12.1481 PMid:14625345

  • Gant TG. Using deuterium in drug discovery: Leaving the label in the drug. Journal of Medicinal Chemistry. 2014; 57(9):3595-611. https://doi.org/10.1021/jm4007998 PMid:24294889

  • Meanwell NA. Synopsis of some recent tactical application of bioisosteres in drug design. Journal of Medicinal Chemistry. 2011; 54(8):2529-91. https://doi.org/10.1021/jm1013693 PMid:21413808

  • Croom E. Metabolism of xenobiotics of human environments. Progress in molecular biology and translational science. 2012; 112:31-88. https://doi.org/10.1016/B978-0-12-415813-9.00003-9 PMid:22974737

  • Timmins GS. Deuterated drugs; updates and obviousness analysis. Expert Opinion on Therapeutic Patents. 2017; 27(12):1353-61. https://doi.org/10.1080/13543776.2017.1378350 PMid:28885861

  • Schmidt C. First deuterated drug approved. Nature Biotechnology. 2017; 35(6):493-5. https://doi.org/10.1038/ nbt0617-493 PMid:28591114

  • Anderson KE, Stamler D, Davis MD, Factor SA, Hauser RA, Isojärvi J, Jarskog LF, Jimenez-Shahed J, Kumar R, McEvoy JP, Ochudlo S. Deutetrabenazine for treatment of involuntary movements in patients with Tardive Dyskinesia (AIM-TD): A double-blind, randomised, placebo-controlled, phase 3 trial. The Lancet Psychiatry. 2017; 4(8):595-604. https://doi.org/10.1016/S2215-0366(17)30236-5 PMid:28668671

  • Citrome L. Breakthrough drugs for the interface between psychiatry and neurology. International Journal of Clinical Practice. 2016; 70(4):298-9. https://doi.org/10.1111/ijcp.12805 PMid:27028671

  • Coppen EM, Roos RA. Current pharmacological approaches to reduce chorea in Huntington’s disease. Drugs. 2017; 77:29-46. https://doi.org/10.1007/s40265-016-0670-4 PMid:27988871 PMCid:PMC5216093

  • Rosenberg R, Roth T, Scharf MB, Lankford DA, Farber R. Efficacy and tolerability of indiplon in transient insomnia. Journal of Clinical Sleep Medicine. 2007; 3(4):374-9. https:// doi.org/10.5664/jcsm.26859 PMid:17694726 PMCid: PMC1978303

  • Harbeson SL, Tung RD. Deuterium in drug discovery and development. Annual Reports in Medicinal Chemistry. Academic Press; 2011. p. 403-417. https://doi.org/10.1016/ B978-0-12-386009-5.00003-5

  • Schneider, Frank, Hillgenberg M, Koytchev R, Alken R-G. Enhanced plasma concentration by selective deuteration of rofecoxib in rats. Arzneimittelforschung. 2006; 56(4):295-300. https://doi.org/10.1055/s-0031-1296724 PMid:16724516

  • Morgan AJ, Pandya BA, Masse CE, Harbeson SL. Old drugs yield new discoveries: Examples from the prodrug, chiral switch, and site‐selective deuteration strategies. Drug Repositioning: Bringing New Life to Shelved Assets and Existing Drugs; 2012. p. 291. https:// doi.org/10.1002/9781118274408.ch10 PMid:23133329 PMCid:PMC3484954

  • Janni M, Peruncheralathan S. Catalytic selective deuteration of halo (hetero) arenes. Organic & Biomolecular Chemistry. 2016; 14(11):3091-7. https://doi.org/10.1039/C6OB00193A PMid:26899945

  • DeWitt SH, Maryanoff BE. Deuterated drug molecules: Focus on FDA-approved deutetrabenazine: Published as part of the biochemistry series “biochemistry to bedside”. Biochemistry. 2018; 57(5):472-3. https://doi.org/10.1021/acs.biochem.7b00765 PMid:29160059

  • Mori T, Ito T, Liu S, Ando H, Sakamoto S, Yamaguchi Y, Tokunaga E, Shibata N, Handa H, Hakoshima T. Structural basis of thalidomide enantiomer binding to cereblon. Scientific Reports. 2018; 8(1):1-4. https://doi. org/10.1038/s41598-018-19202-7 PMid:29358579 PMCid: PMC5778007

  • acques V, Bolze S, Hallakou‐Bozec S, Czarnik AW, Divakaruni AS, Fouqueray P, Murphy AN, Van der Ploeg LH, DeWitt S. Deuterium‐stabilized (R)‐pioglitazone (PXL065) is responsible for pioglitazone efficacy in NASH yet exhibits little to no PPARγ activity. Hepatology Communications. 2021; 5(8):1412-25. https://doi.org/10.1002/hep4.1723 PMid:34430785 PMCid:PMC8369945

  • Maltais F, Jung YC, Chen M, Tanoury J, Perni RB, Mani N, Laitinen L, Huang H, Liao S, Gao H, Tsao H. In vitro and in vivo isotope effects with hepatitis C protease inhibitors: Enhanced plasma exposure of deuterated telaprevir versus telaprevir in rats. Journal of Medicinal Chemistry. 2009; 52(24):7993-8001. https://doi.org/10.1021/jm901023f PMid:19894743

  • Hill S, Lamberson CR, Xu L, To R, Tsui HS, Shmanai VV, Bekish AV, Awad AM, Marbois BN, Cantor CR, Porter NA. Small amounts of isotope-reinforced polyunsaturated fatty acids suppress lipid autoxidation. Free Radical Biology and Medicine. 2012; 53(4):893-906. https://doi. org/10.1016/j.freeradbiomed.2012.06.004 PMid:22705367 PMCid:PMC3437768

  • Lamberson CR, Xu L, Muchalski H, Montenegro-Burke JR, Shmanai VV, Bekish AV, McLean JA, Clarke CF, Shchepinov MS, Porter NA. Unusual kinetic isotope effects of deuterium reinforced polyunsaturated fatty acids in tocopherol-mediated free radical chain oxidations. Journal of the American Chemical Society. 2014; 136(3):838-41. https://doi.org/10.1021/ja410569g PMid:24380377 PMCid: PMC4578730

  • Klein PD, Klein ER. Stable isotopes: origins and safety. The Journal of Clinical Pharmacology. 1986; 26(6):378-82. https://doi.org/10.1002/j.1552-4604.1986.tb03544.x PMid: 3734125

  • Baum D, Dobbing J, Coward WA. Deuterium method for measuring milk intake in babies. Lancet. 1979. https://doi. org/10.1016/S0140-6736(79)90327-1 PMid:88642

  • Butte NF, Wong WW, Klein PD, Garza C. Measurement of milk intake: Tracer-to-infant deuterium dilution method. British Journal of Nutrition. 1991; 65(1):3-14. https://doi.org/10.1079/BJN19910060 PMid:1997129

  • Pons G, Rey E. Stable isotopes labeling of drugs in pediatric clinical pharmacology. Pediatrics. 1999; 104(Supplement_3):633-9. https://doi.org/10.1542/peds. 104. S3.633 PMid:10469806

  • Rodewald LE, Maiman LA, Foye HR, Borch RF, Forbes GB. Deuterium oxide as a tracer for measurement of compliance in pediatric clinical drug trials. The Journal of Pediatrics. 1989; 114(5):885-91. https://doi.org/10.1016/S0022-3476(89)80159-3 PMid:2541239

  • White RD, Gandolfi AJ, Bowden GT, Sipes IG. Deuterium isotope effect on the metabolism and toxicity of 1, 2-dibromoethane. Toxicology and Applied Pharmacology. 1983; 69(2):170-8. https://doi.org/10.1016/0041-008X(83) 90297-1 PMid:6346586

  • Branchflower RV, Nunn DS, Highet RJ, Smith JH, Hook JB, Pohl LR. Nephrotoxicity of chloroform: Metabolism to phosgene by the mouse kidney. Toxicology and Applied Pharmacology. 1984; 72(1):159-68. https://doi. org/10.1016/0041-008X(84)90260-6 PMid:6143425

  • Kushner DJ, Baker A, Dunstall TG. Pharmacological uses and perspectives of heavy water and deuterated compounds. Canadian Journal of Physiology and Pharmacology. 1999; 77(2):79-88. https://doi.org/10.1139/y99-005 PMid: 10535697

  • Carlstedt BC, Crespi HL, Blake MI, Katz JJ. Biosynthesis of deuterated benzylpenicillins III: Relative antibiotic potency of highly deuterated benzylpenicillin. Journal of Pharmaceutical Sciences. 1973; 62(5):856-7. https://doi. org/10.1002/jps.2600620546 PMid:4705709

  • Fischer JJ, Jardetzky O. Nuclear magnetic relaxation study of intermolecular complexes. The mechanism of penicillin binding to serum albumin1a. Journal of the American Chemical Society. 1965; 87(14):3237-44. https://doi. org/10.1021/ja01092a040 PMid:14329431

  • Katz JJ, Crespi HL. Isotope effects in chemical reactions. New York, NY, USA: Van Nostrand Reinhold; 1971.

  • Alffenaar JW, Bolhuis M, Van Hateren K, Sturkenboom M, Akkerman O, de Lange W, Greijdanus B, van der Werf T, Touw D. Determination of bedaquiline in human serum using liquid chromatography-tandem mass spectrometry. Antimicrobial Agents and Chemotherapy. 2015; 59(9):5675-80. https://doi.org/10.1128/AAC.00276-15 PMid:26149993 PMCid:PMC4538542

  • Cox E, Laessig K. FDA approval of bedaquiline- the benefit-risk balance for drug-resistant tuberculosis. New England Journal of Medicine. 2014; 371(8):689-91. https://doi.org/10.1056/NEJMp1314385 PMid:25140952

  • Bhadra PK, Hassanzadeh A, Arsic B, Allison DG, Morris GA, Barber J. Enhancement of the properties of a drug by mono-deuteriation: Reduction of acid-catalysed formation of a gut-motilide enol ether from 8-deuterio-erythromycin B. Organic and Biomolecular Chemistry. 2016; 14(26):6289- 96. https://doi.org/10.1039/C6OB00785F PMid:27273525

  • Norcott P, Rayner PJ, Green GG, Duckett SB. Achieving high 1H nuclear hyperpolarization levels with long lifetimes in a range of tuberculosis drug scaffolds. Chemistry- A European Journal. 2017; 23(67):16990-7. https://doi. org/10.1002/chem.201703278 PMid:28990279

  • Liu R, Krchnak V, Brown SN, Miller MJ. Deuteration of BTZ043 extends the lifetime of meisenheimer intermediates to the antituberculosis nitroso oxidation state. ACS Medicinal Chemistry Letters. 2019; 10(10):1462-6. https:// doi.org/10.1021/acsmedchemlett.9b00308 PMid:31620234 PMCid:PMC6792150

  • Harbeson SL, Tung RD. Deuterium in drug discovery and development. Annual Reports in Medicinal Chemistry. Academic Press; 2011. p. 403-417. https://doi.org/10.1016/ B978-0-12-386009-5.00003-5

  • Reider PJ, Conn RS, Davis P, Grenda VJ, Zambito AJ, Grabowski EJ. Synthesis of (R)-serine-2-d and its conversion to the broad-spectrum antibiotic fludalanine. The Journal of Organic Chemistry. 1987; 52(15):3326-34. https://doi.org/10.1021/jo00391a029

  • Morgan AJ, Pandya BA, Masse CE, Harbeson SL. Old drugs yield new discoveries: Examples from the prodrug, chiral switch, and site‐selective deuteration strategies. Drug Repositioning: Bringing New Life to Shelved Assets and Existing Drugs; 2012. p. 291. https:// doi.org/10.1002/9781118274408.ch10 PMid:23133329 PMCid:PMC3484954

  • Anjana GV, Kathiravan MK. Antimicrobial activity of curcumin and deuterated curcumin. Journal of Natural Remedies. 2022; 22(3):424-31. https://doi.org/10.18311/ jnr/2022/29686

  • Anjana GV. Synthesis and antimicrobial evaluation of deuterated analogues of metronidazole. Iraqi Journal of Pharmaceutical Sciences. 2022; 31(2):297-303. https://doi.org/10.31351/vol31iss2pp297-303


Abstract Views: 160

PDF Views: 74




  • Deuterium - A Natural Isotope to Combat Microbial Resistance

Abstract Views: 160  |  PDF Views: 74

Authors

Nirupama Panda
Dr APJ Abdul Kalam Research Laboratory, Department of Pharmaceutical Chemistry, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur – 603203, Tamil Nadu, India
S. K. Zakki Uddin
Dr APJ Abdul Kalam Research Laboratory, Department of Pharmaceutical Chemistry, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur – 603203, Tamil Nadu, India
G. V. Anjana
Dr APJ Abdul Kalam Research Laboratory, Department of Pharmaceutical Chemistry, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur – 603203, Tamil Nadu, India
P. Ramalingam
Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER) Hajipur District: Vaishali, Hajipur - 844102, Bihar, India
Senthilkumar Palaniappan
Faculty of Pharmacy, Karpagam Academy of Higher Education, Pollachi Main Road, Eachanari Post, Coimbatore - 641021, Tamil Nadu, India
M. K. Mohan Maruga Raja
Department of Pharmacognosy and Phytochemistry, Parul Institute of Pharmacy and Research, Parul University, Vadodara, Gujarat – 391760, India
M. K. Kathiravan
Dr APJ Abdul Kalam Research Laboratory, Department of Pharmaceutical Chemistry, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur – 603203, Tamil Nadu, India

Abstract


Deuterated medicinal chemistry is an attempt to introduce deuterium into existing drug molecules through the replacement of hydrogen atoms (-H) with deuterium (-D). The process of deuteration is to reduce the rates of breaking the carbonhydrogen bond. If the carbon-hydrogen bond breaking is the rate-determining step in the biotransformation of the drug, the deuterated drug may show improved pharmacokinetic characteristics, such as a longer half-life, hence lowering the need for frequent dosing. In this review, we discuss the improvement in the drug’s pharmacokinetic profile with deuterium. Further, this Deuterium exchange chemistry can reduce toxicity and be safe for human use. Also, the drugs experimented with using deuterium are discussed as how deuterated chemistry can help fight antimicrobial resistance. Beyond all, still, the design and development of a successful deuterated drug with acceptable efficacy is hence a challenge. The translation of hypotheses from laboratory experiments to clinical application and further to real-time practice is unpredictable. Also, long-term drug stability and toxicity studies for individual drugs are to be studied which may vary from patient to patient.

Keywords


Antimicrobial Resistance, Deuterium, Metronidazole, Pharmacokinetic Property

References





DOI: https://doi.org/10.18311/%2Fjnr%2F2023%2F31386