Strategically Placed Trifluoromethyl Substituent in the Realm of Antitubercular Drug Design

Author(s): Sidhartha S. Kar , Cinu A. Thomas* .

Journal Name: Current Drug Therapy

Volume 14 , Issue 2 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Fluorinated substituents have played, and continue to play an important role in antitubercular drug design. Nonetheless, previous works have indicated that organofluorines like –F, CF3, -OCF3, and CHF2 etc have been used to modulate the pharmacodynamic and pharmacokinetic behaviour of antitubercular agents. Among the fluorinated groups, trifluoromethyl (-CF3) substituent is a very familiar pharmacophore used widely in antitubercular research.

Objective: This review assesses the development of selected trifluoromethyl group bearing antitubercular agents that are either in treatment or considered to be potential. The prime objective of the present investigation was to provide initial evidences for the hypothesis that addition of trifluoromethyl group to antiTB agents could improve their potency. We also aimed to contribute to a better understanding of the role of trifluoromethyl group on drug-likeness antitubercular activity.

Methods: In this review, we first brief out the possible effect of –CF3 substituent on pharmacodynamic and pharmacokinetic properties of drugs. Next, we turn to emphasize on the effect of trifluoromethyl substituent on different antitubercular scaffolds. Finally, we open the topic for the researchers to design potential antitubercular agents suitably substituted with fluorinated groups.

Results: This review suggests that the replacement of –CF3 group in heterocyclic as well as phenyl ring led to the improvement in pharmacodynamic and pharmacokinetic properties of the compounds. Hence it's not surprising to see –CF3 group emerging as an alternative electron withdrawing group instead of halogens in many promising antitubercular agents.

Conclusion: This unusual spectrum of advantage allied with its lipophilicity enhancing effect, made –CF3 group distinct from other substituents in modern antitubercular drug design. The present study provides conceptual advances to the understanding of the physicochemical properties of –CF3 group and its effect on antitubercular activity.

Keywords: Trifluoromethyl group, antitubercular agents, structure-activity relationships, drug-likeness, pharmacodynamic, pharmacokinetic.

[1]
Bending the curve - ending TB: Annual report 2017 India: World Health Organization, Regional Office for South-East Asia; 2017. Licence: CC BY-NC-SA 3.0 IGO.
[2]
Gill C, Jadhav G, Mohammad Shaikh M, et al. Clubbed [1,2,3] triazoles by fluorine benzimidazole: A novel approach to H37Rv inhibitors as a potential treatment for tuberculosis. Bioorg Med Chem Lett 2008; 18: 6244-7.
[3]
Purser S, Moore PR, Swallow S, Gouverneur V. Fluorine in medicinal chemistry. Chem Soc Rev 2008; 37(2): 320-30.
[4]
Kirk KL. Fluorine in medicinal chemistry: Recent therapeutic applications of fluorinated small molecules. J Fluor Chem 2006; 127: 1013-29.
[5]
Landelle G, Panossian A, Leroux FR. Trifluoromethyl ethers and -thioethers as tools for medicinal chemistry and drug discovery. Curr Top Med Chem 2014; 14(7): 941-51.
[6]
Maccari R, Ottana R, Vigorita MG. In vitro advanced antimycobacterial screening of isoniazid-related hydrazones, hydrazides and cyanoboranes: part 14. Bioorg Med Chem Lett 2005; 15: 2509-13.
[7]
Frédéric RL, Manteau B, Vors JP, Pazenok S. Trifluoromethyl ethers - synthesis and properties of an unusual substituent. Beilstein J Org Chem 2008; 4(13): 1-15.
[8]
Kovacevic B, Maksić ZB, Primorac M. Acidity of substituted benzenes - an ab initio study of the influence of methoxy, trifluoromethyl and trifluoromethoxy groups by a novel trichotomy formula. Eur J Org Chem 2003; 19: 3777-83.
[9]
Wermuth CG. The Practice of Medicinal Chemistry. 3rd ed. Academic Press: New York 2015.
[10]
Banks RE, Smart BE, Tatlow JC. Organofluorine Chemistry Principles and Commercial Applications. 3rd Eds. Plenum Press: New York 1994.
[11]
Muller K, Faeh C, Diederich F. Fluorine in pharmaceuticals: looking beyond intuition. Science 2007; 317: 1881-6.
[12]
Smart BE. Fluorine substituent effects on bioactivity. J Fluor Chem 2001; 109(1): 3-11.
[13]
Bégué JP, Delpon DB. Bioorganic and medicinal chemistry of fluorine. 1st Eds. . Wiley & Sons: New York 2008.
[14]
Castagnetti E, Schlosser M. The trifluoromethoxy group: a long-range electron-withdrawing substituent. Chem A Eur J 2002; 8(4): 799-04.
[15]
Diacon AH, Dawson R, Hanekom M, et al. Early bactericidal activity and pharmacokinetics of PA824 in smear positive tuberculosis patients. Antimicrob Agents Chemother 2010; 54(8): 3402-7.
[16]
Pretomanid, TB Alliance.. https://www.revolvy.com/page/ Pretomanid (Accessed on March 21, 2017).
[17]
Matsumoto M, Hashizume H, Tomishige T, et al. OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice. PLoS Med 2006; 3: 2131-43.
[18]
Hoagland DT, Liu J, Lee RB, Lee RE. New agents for the treatment of drug-resistant Mycobacterium tuberculosis. Adv Drug Deliv Rev 2016; 102: 55-72.
[19]
Upton AM, Cho S, Yang TJ, et al. In vitro and in vivo activities of the nitroimidazole TBA-354 against Mycobacterium tuberculosis. Antimicrob Agents Chemother 2015; 59(1): 13644.
[20]
Pethe K, Bifani P, Jang J, et al. Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nat Med 2013; 19: 1157-60.
[21]
Arora SK, Anuradha K, Avhad AJ. Phase 1 clinical trial of LL-3858 (Sudoterb), a potential candidate for the treatment of MDR tuberculosis. Int J Tuberc Lung Dis 2008; 12: S319.
[22]
Adhvaryu M, Vakharia B. Drug-resistant tuberculosis: emerging treatment Options. Clin Pharmacol 2011; 3: 51-67.
[23]
Makarov V, Manina G, Mikusova K, et al. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science 2009; 324(5928): 801-4.
[24]
Pasca MR, Degiacomi G, Ribeiro AL, et al. Clinical isolates of Mycobacterium tuberculosis in four European hospitals are uniformly susceptible to benzothiazinones. Antimicrob Agents Chemother 2010; 54(4): 1616-8.
[25]
ClinicalTrials. Gov processed this record on June 20, 2017.https://clinicaltrials.gov/ct2 (Accessed on June 25, 2017).
[26]
Bermudez LE, Kolonoski P, Wu M, Aralar PA, Inderlied CB, Young LS. Mefloquine is active in vitro and in vivo against Mycobacterium avium complex. Antimicrob Agents Chemother 1999; 43: 1870-4.
[27]
Nannini EC, Keating M, Binstock P, Samonis G, Kontoyiannis DP. Successful treatment of refractory disseminated Mycobacterium avium complex infection with the addition of linezolid and mefloquine. J Infect 2002; 44(3): 201-3.
[28]
Mao J, Yuan H, Wang Y, et al. Synthesis and antituberculosis activity of novel mefloquine-isoxazole carboxylic esters as prodrugs. Synthesis and anti-tuberculosis activity of novel mefloquine-isoxazole carboxylic esters as prodrugs. Bioorg Med Chem Lett 2010; 20(3): 1263-8.
[29]
Lilienkampf A, Mao J, Wan B, Wang Y, Franzblau SG, Kozikowski AP. Structure-activity relationships for a series of quinoline-based compounds active against replicating and nonreplicating Mycobacterium tuberculosis. J Med Chem 2009; 52(7): 2109-18.
[30]
Mital A, Negi VS, Ramachandran U. Synthesis and antimycobacterial activities of certain trifluoromethyl-amino quinoline derivatives. Arkivoc 2006; 10: 220-7.
[31]
Eswaran S, Adhikari AV, Kumar R. New 1,3-oxazolo[4,5-c]quinoline derivatives: synthesis and evaluation of antibacterial and antituberculosis properties. Eur J Med Chem 2010; 45(3): 957-66.
[32]
Eswaran S, Adhikari AV, Pal NK, et al. Targeting tuberculosis and malaria through inhibition of enoyl reductase: compound activity and structural data. J Biol Chem 2003; 278: 20851-9.
[33]
Kuo MR, Morbidoni HR, Alland D, et al. Targeting tuberculosis and malaria through inhibition of enoyl reductase: compound activity and structural data. J Biol Chem 2003; 278: 20851-9.
[34]
Almeida da Silva PE, Ramosa DF, Bonacorso HG, et al. Synthesis and in vitro antimycobacterial activity of 3-substituted 5-hydroxy-5-trifluoro[chloro]methyl-4,5 dihydro-1 H-1-(isonicotinoyl) pyrazoles. Int J Antimicrob Agents 2008; 32: 139-44.
[35]
Addla D, Jallapally A, Gurram D, Yogeeswari P, Sriram D, Kantevari S. Rational design, synthesis and antitubercular evaluation of novel 2-(trifluoromethyl) phenothiazine-[1,2,3]triazole hybrids. Bioorg Med Chem Lett 2014; 24(1): 233-6.
[36]
Abdel-Rahman HM, El-Koussi NA, Hassan HY. Fluorinated 1,2,4-Triazolo[1,5-a] pyrimidine-6-carboxylic acid derivatives as antimycobacterial agents. Arch Pharm Chem Life Sci 2009; 342(2): 94-9.
[37]
Šink R, Sosi I, Živec M, et al. Design, synthesis and evaluation of new thiadiazolebased direct inhibitors of enoyl acyl carrier protein reductase (InhA) for the treatment of tuberculosis. J Med Chem 2015; 58(2): 613-24.
[38]
Yokokawa F, Wang G, Chan WL, et al. Discovery of tetrahydropyrazolopyrimidine carboxamide derivatives as potent and orally active antitubercular agents. ACS Med Chem Lett 2013; 4(5): 451-5.
[39]
Onajole OK, Pieroni M, Tipparaju SK, et al. Preliminary structure-activity relationships and biological evaluation of novel antitubercular indolecarboxamide derivatives against drug-susceptible and drug-resistant Mycobacterium tuberculosis strains. J Med Chem 2013; 56: 4093-3.
[40]
Maccari R, Ottana R, Monforte F, Vigorita MG. In vitro antimycobacterial activities of 2′-monosubstituted isonicotinohydrazides and their cyanoborane adducts. Antimicrob Agents Chemother 2002; 46(2): 294-9.
[41]
Güzel O, Karali N, Salman A. Synthesis and antituberculosis activity of 5-methyl/trifluoromethoxy-1H-indole-2,3-dione 3-thiosemicarbazone derivatives. Bioorg Med Chem 2008; 16: 8976-87.
[42]
Palmer BD, Thompson AM, Sutherland HS, et al. Synthesis and structure-activity studies of biphenyl analogues of the tuberculosis drug (6s)-2-nitro-6-[4-(trifluoromethoxy) benzyl]oxy-6,7-dihydro-5h-imidazo[2,1-b][1,3]oxazine (PA-824). J Med Chem 2010; 53: 282-94.
[43]
Sriram D, Yogeeswari P, Dinakaran M, Thirumurugan R. Antimycobacterial activity of novel 1-(5-cyclobutyl-1,3-oxazol-2-yl)-3-(sub)phenyl/pyridylthiourea compounds endowed with high activity toward multidrug-resistant Mycobacterium tuberculosis. J Antimicrob Chemother 2007; 59: 1194-6.
[44]
Lilienkampf A, Pieroni M, Wan B, Wang Y, Franzblau SG, Kozikowski AP. Rational design of 5-phenyl-3-isoxazolecarboxylic acid ethyl esters as growth inhibitors of Mycobacterium tuberculosis: a potent and selective series for further drug development. J Med Chem 2010; 53: 678-88.
[45]
Yang Y, Wang Z, Yang J, et al. Design, synthesis and evaluation of novel molecules with a diphenyl ether nucleus as potential antitubercular agents. Bioorg Med Chem Lett 2012; 22: 954-7.
[46]
Guo S, Song Y, Huang Q, et al. Identification, synthesis, and pharmacological evaluation of tetrahydroindazole based ligands as novel antituberculosis agents. J Med Chem 2010; 53: 649-59.
[47]
Dolezal M, Cmedlova P, Palek L, et al. Synthesis and antimycobacterial evaluation of substituted pyrazinecarboxamides. Eur J Med Chem 2008; 43(5): 1105-13.
[48]
Zhang D, Lu Y, Liu K, et al. Identification of less lipophilic riminophenazine derivatives for the treatment of drug-resistant tuberculosis. J Med Chem 2012; 55(19): 8409-17.
[49]
Krátký M, Vinšová J, Novotná E, et al. Salicylanilide derivatives block Mycobacterium tuberculosis through inhibition of isocitrate lyase and methionine aminopeptidase. Tuberculosis 2012; 92: 434-9.
[50]
Krátký M, Vinšová J, Novotná E, Mandíková J, Trejtnar F, Stolaříková J. Antibacterial activity of salicylanilide 4-(trifluoromethyl) benzoates. Molecules 2013; 18: 3674-88.
[51]
Sun D, Scherman MS, Jones V, et al. Discovery, synthesis, and biological evaluation of piperidinol analogs with anti-tuberculosis activity. Bioorg Med Chem 2009; 17(10): 3588-94.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 14
ISSUE: 2
Year: 2019
Page: [114 - 123]
Pages: 10
DOI: 10.2174/1574885513666180906101732
Price: $58

Article Metrics

PDF: 23
HTML: 4
EPUB: 1
PRC: 2