Antibiotics Are Man's Greatest Invention

Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors

  • 1.

    Askari BS, Krajinovic M. Dihydrofolate reductase gene variations in susceptibility to disease and treatment outcomes. Curr Genom. 2010;11:578–83.

  • 2.

    Schnell JR, Dyson HJ, Wright PE. Structure, dynamics, and catalytic function of dihydrofolate reductase. Annu Rev Biophys Biomol Struct. 2004;33:119–40.

  • 3.

    Schweitzer B, Dicker AP, Bertino JR. Dihydrofolate reductase as a therapeutic target. FASEB J. 1990;4:2441–52.

  • 4.

    Blakley RL. Eukaryotic dihydrofolate reductase. Adv Enzymol Relat Areas Mol Biol. 1995;70:23–102.

  • 5.

    Heaslet H, Harris M, Fahnoe K, et al. Structural comparison of chromosomal and exogenous dihydrofolate reductase from Staphylococcus aureus in complex with the potent inhibitor trimethoprim. Proteins. 2009;76:706–17.

  • 6.

    Hong W, Wang Y, Chang Z. The identification of novel Mycobacterium tuberculosis DHFR inhibitors and the investigation of their binding preferences by using molecular modelling. Sci Rep. 2015;16:15328.

  • 7.

    Rashid N, Thapliyal C, Chaudhuri P. Dihydrofolate reductase as a versatile drug target in healthcare. JPP. 2016;7:247–57.

  • 8.

    Bhosle A, Chandra N. Structural analysis of dihydrofolate reductases enables rationalization of antifolate binding affinities and suggests repurposing possibilities. FEBS J. 2016;283:1139–67.

  • 9.

    Selassie CD, Li RL, Poe MR, Hansch C. Optimization of hydrophobic and hydrophilic substituent interactions of 2,4-diamino-5-(substituted-benzyl)pyrimidines with dihydrofolate reductase. J Med Chem. 1991;34:46–54.

  • 10.

    Nammalwar B, Bourne CR, Wakeham N. Modified 2,4‐diaminopyrimidine‐based dihydrofolate reductase inhibitors as potential drug scaffolds against Bacillus anthracis. Bioorg Med Chem. 2015;23:203–11.

  • 11.

    Nelson RG, Rosowsky A. Dicyclic and tricyclic diaminopyrimidine derivatives as potent inhibitors ofCryptosporidiumparvumdihydrofolate reductase: structure‐activity and structure‐selectivity correlations. Antimicrob Agents Chemother. 2001;45:3293–303.

  • 12.

    Srinivasan B, Skolnick J. Insights into the slow‐onset tight‐binding inhibition of Escherichia colidihydrofolatereductase: detailed mechanistic characterization of pyrrolo [3,2‐f] quinazoline‐1,3‐diamine and its derivatives as novel tight‐binding inhibitors. FEBS J. 2015;282:1922–38.

  • 13.

    Jackson HC, Biggadike K, McKilligin E, et al. 6,7‐disubstituted 2,4‐diaminopteridines: novel inhibitors of Pneumocystis carinii and Toxoplasma gondiidihydrofolate reductase. Antimicrob Agents Chemother. 1996;40:1371–5.

  • 14.

    Sinivasan B, Tonddast‐Navaei S, Skolnick J. Ligand binding studies, preliminary structure‐activity relationship and detailed mechanistic characterization of 1‐phenyl‐6,6‐dimethyl‐1,3,5‐triazine‐2,4‐diamine derivatives as inhibitors of Escherichia coli dihydrofolate reductase. Eur J Med Chem. 2015;103:600–14.

  • 15.

    Srinivasan B, Tonddast-Navaei S, Roy A, Zhou H, Skolnick J. Chemical space of Escherichia coli dihydrofolate reductase inhibitors: New approaches for discovering novel drugs for old bugs. Med Res Rev. 2019;39:684–705.

  • 16.

    Roth B, Falco EA, Hitchings GH, Bushby SRM. 5-benzyl-2,4-diaminopyrimidines as antibacterial agents.I. Synthesis and Antibacterial Activity in vitro. J Med Pharm Chem. 1962;5:1103–23.

  • 17.

    Skold O. Resistance to trimethoprim and sulfonamides. Vet Res. 2011;32:261–73.

  • 18.

    Burchall JJ. The development of the diaminopyrimidines. J Antimicrob Chemother. 1979;5:3–14.

  • 19.

    Capasso C, Supuran CT. Sulfa and trimethoprim-like drugs—antimetabolites acting as carbonic anhydrase, dihydropteroate synthase and dihydrofolate reductase inhibitors. J Enzym Inhib Med Chem. 2014;29:379–87.

  • 20.

    Matthews DA, Bolins JT, Burridge JM, Filmann DJ, Volzll KW, Kraut J. Dihydrofolate reductase. the stereochemistry of inhibitor selectivity. J Biol Chem. 1985;260:392–9.

  • 21.

    Darrell JH, Garrod LP, Waterworth PM. Trimethoprim: laboratory and clinical studies. J Clin Pathol. 1968;21:202–9.

  • 22.

    Kasanen A, Sundquist H. Trimethoprim alone in the treatment of urinary tract infections: eight years of experience in Finland. Rev Infect Dis. 1982;4:358–65.

  • 23.

    Lacey RW. Do sulphonamide-trimethoprim combinations select less resistance to trimethoprim than the use of trimethoprim alone? J Med Microbiol. 1982;15:403–27.

  • 24.

    Huovinen P, Sundström L, Swedberg G, Sköld O. Trimethoprim and sulfonamide resistance. Antimicrob Agents Chemother. 1995;39:279–89.

  • 25.

    Noall EW, Sewards HF, Waterworth PM. Successful treatment of a case of Proteus septicaemia. Br Med J. 1962;2:1101–2.

  • 26.

    Bushby SR. Trimethoprim-sulfamethoxazole: in vitro microbiological aspects. J Infect Dis. 1973;128:442–62.

  • 27.

    Taur Y, Smith MA. Adherence to the infectious diseases society of America guidelines in the treatment of uncomplicated urinary tract infection. Clin Infect Dis. 2007;44:769–74.

  • 28.

    Navarro-Martínez MD, Cabezas-Herrera J, Rodríguez-López JN. Antifolates as antimycotics? a connection between the folic acid cycle and the ergosterol biosynthesis pathway in Candida albicans. Int J Antimicrob Agents. 2006;28:560–7.

  • 29.

    Kahlmeter G. An international survey of the antimicrobial susceptibility of pathogens from uncomplicated urinary tract infections: the ECO.SENS Project. J Antimicrob Chemother. 2003;51:69–76.

  • 30.

    Kahlmeter G, Poulsen HO. Antimicrobial susceptibility of Escherichia coli from community-acquired urinary tract infections in Europe: the ECO.SENS study revisited. Int J Antimicrob Agents. 2012;39:45–51.

  • 31.

    Naber KG, Schito G, Botto H, Palou J, Mazzei T. Surveillance study in Europe and Brazil on clinical aspects and Antimicrobial Resistance Epidemiology in Females with Cystitis (ARESC): implications for empiric therapy. Eur Urol. 2008;54:1164–75.

  • 32.

    Crider SR, Colby SD. Susceptibility of enterococci to trimethoprim and trimethoprim-sulfamethoxazole. Antimicrob Agents Chemother. 1985;27:71–5.

  • 33.

    Hamilton-Miller JM. Reversal of activity of trimethoprim against gram-positive cocci by thymidine, thymine and ‘folates. J Antimicrob Chemother. 1998;22:35–9.

  • 34.

    Maskell JP, Sefton AM, Hall LMC. Multiple mutations modulate the function of dihydrofolate reductase in trimethoprim-resistant Streptococcus pneumoniae. Antimicrob Agents Chemother. 2001;45:1104–8.

  • 35.

    Salter AJ. Trimethoprim-sulfamethoxazole: an assessment of more than 12 years of use. Rev Infect Dis. 1982;4:196–236.

  • 36.

    Allegra CJ, Kovacs JA, Drake JC, Swan JC, Chabner BA, Masur H. Activity of antifolates against Pneumocystis carinii dihydrofolate reductase and identification of a potent new agent. J Exp Med. 1987;165:926–31.

  • 37.

    Hooton TM, Besser R, Foxman B, Fritsche TR, Nicolle LE. Acute uncomplicated cystitis in an era of increasing antibiotic resistance: a proposed approach to empirical therapy. Clin Infect Dis. 2004;39:75–80.

  • 38.

    Wormser GP, Keusch GT. Drugs five years later: trimethoprim-sulfamethoxazole in the United States. Ann Intern Med. 1979;91:420–9.

  • 39.

    Stuck AK, Täuber MG, Schabel M, Lehmann T, Suter H, Mühlemann K. Determinants of quinolone versus trimethoprim-sulfamethoxazole use for outpatient urinary tract infection. Antimicrob Agents Chemother. 2012;56:1359–63.

  • 40.

    Afeltra J, Meis JF, Mouton JW, Verweij PE. Prevention of invasive aspergillosis in AIDS by sulfamethoxazole. AIDS. 2001;15:1067–8.

  • 41.

    Afeltra J, Meis JF, Vitale RG, Mouton JW, Verweij PE. In vitro activities of pentamidine, pyrimethamine, trimethoprim, and sulfonamides against Aspergillus species. Antimicrob Agents Chemother. 2002;46:2029–31.

  • 42.

    Hanafy A, Uno J, Mitani H, Kang Y, Mikami Y. In-vitro antifungal activities of sulfa drugs against clinical isolates of Aspergillus and Cryptococcus species. Nihon Ishinkin Gakkai Zasshi. 2007;48:47–50.

  • 43.

    Ajayi BG, Osuntokun B, Olurin O, Kale OO, Junaid TA. Orbital histoplasmosis due to Histoplasma capsulatum var. duboisii: successful treatment with Septrin. J Trop Med Hyg. 1986;89:179–87.

  • 44.

    Egere JU, Gugnani HC, Okoro AN, Suseelan AV. African histoplasmosis in Eastern Nigeria: report of two culturally proven cases treated with spectrin and amphotericin B. J Trop Med Hyg. 1978;81:225–9.

  • 45.

    Brilhante RS, Fechine MA, Cordeiro RA, et al. In vitro effect of sulfamethoxazole-trimethoprim against Histoplasma capsulatum var. capsulatum. Antimicrob Agents Chemother. 2010;54:3978–9.

  • 46.

    Amyes SGB, Towner KJ. Trimethoprim resistance: epidemiology and molecular aspects. J Med Microbiol. 1990;31:1–19.

  • 47.

    Smith HW. Mutants of Klebsiella pneumoniae resistant to several antibiotics. Nature. 1976;259:307–8.

  • 48.

    Traub WH, Kleber I. Selected and spontaneous variants of Serratia marcescens with combined resistance against chloramphenicol, nalidixic acid, and trimethoprim. Chemotherapy. 1977;23:436–51.

  • 49.

    Flensburg J, Skold O. Massive overproduction of dihydrofolate reductase in bacteria as a response to the use of trimethoprim. Eur J Biochem. 1987;162:473–6.

  • 50.

    Goldstein FW, Papadopoulou B, Acar JF. The changing pattern of trimethoprim resistance in Paris, with a review of the worldwide experience. Rev Infect Dis. 1986;8:725–37.

  • 51.

    Hamilton-Miller JMT Resistance to antibacterial agents acting on antifolate metabolism. In: Bryan LE, Eds. Antimicrobial drug resistance. New York: Academic Press; 1984 173–90.

  • 52.

    Smith DR, Calvo JM. Nucleotide sequence of dihydrofolate reductase genes from trimethoprim-resistant mutants of Escherichia coli. Mol Gen Genet. 1982;187:72–8.

  • 53.

    Then RL. Mechanisms of resistance to trimethoprim, the sulfonamides, and trimethoprim-sulfamethoxazole. Rev Infect Dis. 1982;4:261–9.

  • 54.

    Podnecky NL, Wuthiekanun V, Peacock SJ, Schweizer HP. The BpeEF-OprC efflux pump is responsible for widespread trimethoprim resistance in clinical and environmental Burkholderia pseudomallei isolates. Antimicrob Agents Chemother. 2013;57:4381–6.

  • 55.

    White PA, McIver CJ, Rawlinson WD. Integrons and gene cassettes in the enterobacteriaceae. Antimicrob Agents Chemother. 2001;45:2658–61.

  • 56.

    Grape M, Farra A, Kronvall G, Sundstrom L. Integrons and gene cassettes in clinical isolates of co-trimoxazole-resistant Gram-negative bacteria. Clin Microbiol Infect. 2005;11:185–92.

  • 57.

    Blahna MT, Zalewski CA, Reuer J, Kahlmeter G, Foxman B, Marrs CF. The role of horizontal gene transfer in the spread of trimethoprim-sulfamethoxazole resistance among uropathogenic Escherichia coli in Europe and Canada. J Antimicrob Chemother. 2006;57:666–72.

  • 58.

    Dionisio F, Matic I, Radman M, Rodrigues OR, Taddei F. Plasmids spread very fast in heterogeneous bacterial communities. Genetics. 2002;162:1525–32.

  • 59.

    Huovinen P. Trimethoprim resistance. Antimicrob Agents Chemother. 1987;31:1451–6.

  • 60.

    Dale GE, Broger C, D’Arcy A, et al. A single amino acid substitution in Staphylococcus aureus dihydrofolate reductase determines trimethoprim resistance. J Mol Biol. 1997;266:23–30.

  • 61.

    Pikis A, Donkersloot JA, Rodriquez WJ, Keith JM. A conservative amino acid mutation in the chromosome-encoded dihydrofolate reductase confers trimethoprim resistance in Streptococcus pneumoniae. J Infect Dis. 1998;178:700–6.

  • 62.

    Eliopoulos GM, Huovinen P. Resistance to trimethoprim-sulfamethoxazole. Clin Infect Dis. 2001;32:1608–14.

  • 63.

    Adrian PV, Klugman KP. Mutations in the dihydrofolate reductase gene of trimethoprim-resistant isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother. 1997;41:2406–13.

  • 64.

    De Groot R, Sluijter M, de Bruyn A, et al. Genetic characterization of trimethoprim resistance in Haemophilus influenzae. Antimicrob Agents Chemother. 1996;40:2131–6.

  • 65.

    Dale GE, Broger C, Hartman PG, et al. Characterization of the gene for the chromosomal dihydrofolate reductase (DHFR) of Staphylococcus epidermidis ATCC 14990: the origin of the trimethoprim-resistant S1 DHFR from Staphylococcus aureus? J Bacteriol. 1995;177:2965–70.

  • 66.

    Bergmann R, van der Linden M, Chhatwal GS, Nitsche-Schmitz DP. Factors that cause trimethoprim resistance in Streptococcus pyogenes. Antimicrob Agents Chemother. 2014;58:2281–8.

  • 67.

    Bergmann R, Sagar V, Nitsche-Schmitz DP, Chhatwal GS. First detection of trimethoprim resistance determinant dfrG in Streptococcus pyogenes clinical isolates in India. Antimicrob Agents Chemother. 2012;56:5424–5.

  • 68.

    Dale GE, Langen H, Page MG, Then RL, Stuber D. Cloning and characterization of a novel, plasmid-encoded trimethoprim-resistant dihydrofolate reductase from Staphylococcus haemolyticus MUR313. Antimicrob Agents Chemother. 1995;39:1920–4.

  • 69.

    Rouch DA, Messerotti LG, Loo LS, Jackson CA, Skurray LA. Trimethoprim resistance transposon Tn4003 from Staphylococcus aureus encodes genes for a dihydrofolate reductase and thymidylate synthetase flanked by three copies of IS257. Mol Microbiol. 1989;3:161–75.

  • 70.

    Coque TM, Singh KW, Weinstock GM, Murray BE. Characterization of dihydrofolate reductase genes from trimethoprim-susceptible and trimethoprim-resistant strains of Enterococcus faecalis. Antimicrob Agents Chemother. 1999;43:141–7.

  • 71.

    Lee JC, Oh JY, Cho JW, et al. The prevalence of trimethoprim-resistance-conferring dihydrofolate reductase genes in urinary isolates of Escherichia coli in Korea. J Antimicrob Chemother. 2001;47:599–604.

  • 72.

    Tang Y, Shen P, Liang W, Jin J, Jiang X. A putative multi-replicon plasmid co-harboring beta-lactamase genes blaKPC-2, blaCTX-M-14 and blaTEM-1 and trimethoprim resistance gene dfrA25 from a Klebsiella pneumoniae sequence type (ST) 11 strain in China. PLoS ONE. 2017;12:e0171339.

  • 73.

    Bossé JT, Li Y, Walker S, et al. Langford Identification of dfrA14 in two distinct plasmids conferring trimethoprim resistance in Actinobacilluspleuropneumoniae. J Antimicrob Chemother. 2015;70:2217–22.

  • 74.

    Sekiguchi J, Tharavichitkul P, Miyoshi-Akiyama T. al. Cloning and characterization of a novel trimethoprim-resistant dihydrofolate reductase from a nosocomial isolate of Staphylococcus aureus CM.S2 (IMCJ1454). Antimicrob Agents Chemother. 2005;49:3948–51.

  • 75.

    Wang M, Yang J, Yuan M, Xue L, Li H, Tian C, et al. Synthesis and antiproliferative activity of a series of novel 6-substituted pyrido[3,2-d]pyrimidines as potential nonclassical lipophilic antifolates targeting dihydrofolate reductase. Eur J Med Chem. 2017;128:88–97.

  • 76.

    Gangjee A, Mavandadi F, Kisliuk RL, Queener SF. Synthesis of classical and nonclassical 2-amino-4-oxo-6-methyl-5-substituted pyrrolo[2,3-d]pyrimidine antifolate inhibitors of thimidale synthase. J Med Chem. 1999;42:2272–9.

  • 77.

    Burchall JJ, Hitchings GH. Inhibitor binding analysis of dihydrofolate reductases from various species. Inhibitor binding analysis of dihydrofolate reductases from various species. Mol Pharm. 1965;1:126–36.

  • 78.

    McKeage K, Scott L. Atovaquone/Proguanil: A revives of its use for the prophylaxis of Plasmodium falciparum malaria. Drugs. 2003;63:597–623.

  • 79.

    Elsheikha HM. Congenital toxoplasmosis: priorities for further health promotion action. Public Health. 2008;122:335–53.

  • 80.

    Welsch ME, Zhou J, Gao Y, Yan Y, Porter G, Agnihotri G, et al. Discovery of potent and selective leads against toxoplasma gondii dihydrofolate reductase via structure-based design. ACS Med Chem Lett. 2016;7:1124–9.

  • 81.

    Sharma H, Landau MJ, Vargo MA, Spasov KA, Anderson KS. First threedimensional structure of Toxoplasma gondii thymidylate synthase-dihydrofolate reductase: insights for catalysis, interdomain interactions, and substrate channeling. Biochemistry. 2013;52:7305–17.

  • 82.

    Hopper AT, Brockman A, Wise A, Gould J, Barks J, Radke JB, et al. Discovery of selective toxoplasma gondii dihydrofolate reductase inhibitors for the treatment of toxoplasmosis. J Med Chem. 2019;62:1562–76.

  • 83.

    https://www.amazon.com/Antibiotic-Chemotherapy-Book-Expert-Consult-ebook/dp/B0055XI3GA- (ACCESS: FEBRUARY, 2019).

  • 84.

    Tonelli M, Naesens L, Gazzarrini S, Santucci M, Cichero E, Tasso B. Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus. Eur J Med Chem. 2017;135:467–78.

  • 85.

    Braunsteiner AR, Finsinger F. Brodimoprim: therapeutic efficacy and safety in the treatment of bacterial infections. J Chemother. 1993;5:507–11.

  • 86.

    Peppard WJ, Schuenke CD. Iclaprim, a diaminopyrimidine dihydrofolate reductase inhibitor for the potential treatment of antibiotic-resistant staphylococcal infections. Curr Opin Investig Drugs. 2018;9:210–25.

  • 87.

    Schneider P, Hawser S, Islam K. Iclaprim, a novel diaminopyrimidine with potent activity on trimethoprim sensitive and resistant bacteria. Bioorg Med Chem Lett. 2003;13:4217–21.

  • 88.

    Oefner C, Bandera M, Haldimann A, Laue H, Schulz H, Mukhija S, et al. Increased hydrophobic interactions of iclaprim with Staphylococcus aureus dihydrofolate reductase are responsible for the increase in affinity and antibacterial activity. J Antimicrob Chemother. 2009;63:687–98.

  • 89.

    Sincak CA, Schmidt JM. Iclaprim, a novel diaminopyrimidine for the treatment of resistant Gram-positive infections. Ann Pharmacother. 2009;43:1107–14.

  • 90.

    Andrews J, Honeybourne D, Ashby J, et al. Concentrations in plasma, epithelial lining fluid, alveolar macrophages and bronchial mucosa after a single intravenous dose of 1.6 mg/kg of iclaprim (AR-100) in healthy men. J Antimicrob Chemother. 2007;60:677–80.

  • 91.

    Laue H, Valensise T, Seguin A, Lociuro S, Islam K, Hawser S. In the vitro bactericidal activity of iclaprim in human plasma. Antimicrob Agents Chemother. 2009;53:4542–4.

  • 92.

    Peppard WJ, Schuenke CDIclaprim. a diaminopyrimidinedihydrofolate reductase inhibitor for the potential treatment of antibiotic-resistant staphylococcal infections. Curr Opin Investig Drugs. 2008;9:210–25.

  • 93.

    Wyss PC, Gerber P, Hartman PG, et al. Novel dihydrofolate reductase inhibitors. structure-based versus diversity-based library design and high- throughput synthesis and screening. J Med Chem. 2003;46:2304–12.

  • 94.

    Then RL. Antimicrobial dihydrofolate reductase inhibitors—achievements and future options: review. Rev J Chemother. 2004;16:3–12.

  • 95.

    Rashid U, Ahmad W, Hassan FS, et al. Design, synthesis, antibacterial, activity and docking study of some new trimethoprim derivatives. Bioorg Med Chem Lett. 2016;26:5749–53.

  • 96.

    Morgan J, Haritakul R, Keller PA. Antimalarial activity of 2, 4-diaminopyrimidines. Lett Drug Des Discov. 2008;5:277–80.

  • 97.

    Warhurst D. Antimalarial drug discovery: development of inhibitors of dihydrofolate reductase active in drug resistance. Drug Discov Today. 1998;3:538–46.

  • 98.

    Canfield CJ, Milhous WK, Ager AL, Rossan RN, Sweeney TR, Lewis NJ, et al. Ps-15: A potent, orally active antimalarial from a new class of folic acid antagonists. Am J Trop Med Hyg. 1993;49:121–6.

  • 99.

    Tarnchompoo B, Sirichaiwat C, Phupong W, et al. Development of 2,4-diaminopyrimidines as antimalarials based on inhibition of the S108N and C59R+S108N mutants of dihydrofolate reductase from pyrimethamine-resistant Plasmodium falciparum. J Med Chem. 2002;45:1244–52.

  • 100.

    Shaikh MS, Rana J, Gaikwad D, et al. Antifolate agents against wild and mutant strains of Plasmodium falciparum. Indian J Pharm Sci. 2014;76:116–24.

  • 101.

    Roth B, Strelitz JZ, Rauckman BS. 2,4-Diamino-5-benzylpyrimidines and analogues as antibacterial agents. 2. C-Alkylation of pyrimidines with Mannich bases and application to the synthesis of trimethoprim and analogues. J Med Chem. 1980;23:379–84.

  • 102.

    Roth B, Strelitz JZ. Protonation of 2, 4-diaminopyrimidines. I. Dissociation constants and substituent effects. J Org Chem. 1969;34:821.

  • 103.

    Rauckman BS, Roth B. 2,4-Diamino-5-benzylpyrimidines and analogues as antibacterial agents. 3. C-Benzylation of aminopyridines with phenolic Mannich bases. Synthesis of 1- and 3-deaza analogues of trimethoprim. J Med Chem. 1980;23:384–91.

  • 104.

    Roth B, Aig E, Rauckman BS, et al. 2, 4-Diamino-5-benzylpyrimidines and analogues as antibacterial agents. 5. 3’,5’-Dimethoxy-4’-substituted-benzyl analogues of trimethoprim. J Med Chem. 1981;24:933–41.

  • 105.

    Kompis I, Then R, Boehni E, Rey-Bellet G, Zanetti G, Montavon M. Synthesis and antimicrobial activity of C(4’)-substituted analogs of trimethoprim. Eur J Med Chem. 1980;15:17.

  • 106.

    Stuart A, Paterson T, Roth B, Aig E. 2,4-diamino-5-benzylpyrimidines and analogues as antibacterial agents. 6. One-Step synthesis of new trimethoprim derivatives and activity analysis by molecular modeling. J Med Chem. 1983;26:667–73.

  • 107.

    Roth B, Rauckman BS, Ferone R, Baccanari DP, Champness JN, Hyde RM. 2,4-Diamino-5-benzylpyrimidines as antibacterial agents. 7. Analysis of the effect of 3,5-dialkyl substituent size and shape on binding to four different dihydrofolate reductase enzymes. J Med Chem. 1987;30:348–56.

  • 108.

    Roth B, Aig E. 2,4-Diamino-5-benzylpyrimidines as antibacterial agents. 8. The 3,4,5-triethyl isostere of trimethoprim. A Study Specificity. J Med Chem. 1987;30:1998–2004.

  • 109.

    Roth B, Baccanari DP, Sigel CW, et al. 2,4-Diamino-5-benzylpyrimidines and analogues as antibacterial agents. 9. Lipophilic trimethoprim analogues as antigonococcal agents. J Med Chem. 1988;31:122–9.

  • 110.

    Rauckman BS, Tidwell MY, Johnson JV, Roth B. 2,4-Diamino-5-benzylpyrimidines and analogues as antibacterial agents. 10. 2,4-Diamino-5-(6-quinolylmethyl)- and -[(tetrahydro-6-quinolyl) methyl]pyrimidine derivatives. Further specificity studies. J Med Chem. 1989;32:1927–35.

  • 111.

    Painter GR, Grunwald R, Roth B. Interaction of the antifolate antibiotic trimethoprim with phosphatidylcholine membranes: a 13C and 31P nuclear magnetic resonance study. Mol Pharm. 1988;33:551.

  • 112.

    Davis SE, Rauckman BS, Chan JH, Roth B. 2,4-Diamino-5-benzylpyrimidines and analogues as antibacterial agents. 11. Quinolylmethyl analogues with basic substituents conveying specificity. J Med Chem. 1989;32:1936–42.

  • 113.

    Johnson JV, Rauchman BS, Baccanari DP, Roth B. 2,4-Diamino-5-benzylpyrimidines and analogues as antibacterial agents. 12. 1,2-Dihydroquinolylmethyl analogues with high activity and specificity for bacterial dihydrofolate reductase. J Med Chem. 1989;32:1942–9.

  • 114.

    Roth B, Tidwell MY, Ferone R, et al. 2,4-Diamino-5-benzylpyrimidines as antibacterial agents. 13. Some alkenyl derivatives with high in vitro co activity against anaerobic organisms. J Med Chem. 1989;32:949–58.

  • 115.

    Roth B, Cheng CC. Recent progress in the medicinal chemistry of 2,4-diaminopyrimidines. Prog Med Chem. 1982;19:269–331.

  • 116.

    Masur H. Problems in the management of opportunistic infections in patients infected with human immunodeficiency virus. J Infect Dis. 1990;161:858–64.

  • 117.

    Masur H, Brooks JT, Benson CA, Holmes KK, Pau AK, Kaplan JE. Prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: updated Guidelines from the Centers for Disease Control and Prevention, National Institutes of Health, and HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014;58:1308–11.

  • 118.

    Yoon C, Subramanian A, Chi A, et al. Dihydropteroate synthase mutations in pneumocystis pneumonia: impact of applying different definitions of prophylaxis, mortality endpoints and mutant in a single Cohort. Med Mycol. 2013;51:568–75.

  • 119.

    Huang L, Crothers K, Atzori C, et al. Dihydropteroate synthase gene mutations in pneumocystis and sulfa resistance. Emerg Infect Dis. 2004;10:1721–8.

  • 120.

    Ponce CA, Chabe M, George C, et al. High prevalence of pneumocystis jirovecii dihydropteroate synthase gene mutations in patients with a first episode of Pneumocystis pneumonia in Santiago, Chile, and clinical response to trimethoprim-sulfamethoxazole therapy. Antimicrob Agents Chemother. 2017;61:e01290–16.

  • 121.

    Dosso M, Ouattara L, Cherif AM, Bouzid SA, Haller L, Fernex M. Experimental in vitro efficacy study on the interaction of epiroprim plus isoniazid against Mycobacterium tuberculosis. Chemotherapy. 2001;47:123–7.

  • 122.

    Queener SF. New drug developments for opportunistic infections in immunocompromised patients: Pneumocystis carinii. J Med Chem. 1995;38:4739–59.

  • 123.

    Then RL, Hartman PG, Kompis I, Santi D Selective inhibition of dihydrofolate reductase from problem human pathogens. In: Ayling JE, et al. editors. Chemistry and Biology of Pteridines and Folates. New York: Plenum Press 1993. 533–6.

  • 124.

    Rosowsky A, Forsch RA, Queener SF. Inhibition of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductases by 2,4-diamino-5-[2-methoxy-5-(omega-carboxyalkoxy)benzyl]pyrimidines: marked improvement in potency relative to trimethoprim and species selectivity relative to piritrexim. J Med Chem. 2002;45:233–41.

  • 125.

    Rosowsky A, Chen H, Fu H, Queener SF. Synthesis of new 2,4-diaminopyrido[2,3-d] pyrimidine and 2,4-diaminopyrrolo[2,3-d]pyrimidine inhibitors of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductase. Bioorg Med Chem. 2003;11:59–67.

  • 126.

    Kuyper LF, Roth B, Baccanari DP, Ferone R, Beddell CR, Champness JN, et al. Receptor-based design of dihydrofolate reductase inhibitors: comparison of crystallographically determined enzyme-binding with enzyme affinity in a series of carboxy-substituted trimethoprim analogues. J Med Chem. 1985;28:303–11.

  • 127.

    Chan DCM, Fu H, Forsch RA, Queener SF. Design, synthesis, and antifolate activity of new analogues of piritrexim and other diaminopyrimidine dihydrofolate reductase inhibitors with ω-carboxyalkoxy or ω-carboxy-1-alkynyl substitution in the side chain. J Med Chem. 2005;48:4420–31.

  • 128.

    Forsch RA, Queener SF, Rosowsky A. Preliminary in vitro studies on two potent, water-soluble trimethoprim analogues with exceptional species selectivity against dihydrofolate reductase from Pneumocystis carinii and Mycobacterium avium. Bioorg Med Chem Lett. 2004;14:1811–5.

  • 129.

    Rosowsky A, Forsch RA, Queener SF. Further studies on 2,4-diamino-5-(2′,5′-disubstituted benzyl)pyrimidines as potent and selective inhibitors of dihydrofolate reductases from three major opportunistic pathogens of AIDS. J Med Chem. 2003;46:1726–36.

  • 130.

    Davies WL, Grunert RR, Haff RF, et al. Antiviral activity of 1-adamantanamine (amantadine). Science. 1964;144:862–3.

  • 131.

    Orzeszko B, Kazimierczuk Z, Maurin JK, et al. Novel adamantylated pyrimidines and their preliminary biological evaluations. Farmaco. 2004;59:929–37.

  • 132.

    Orzeszko B, Laudy AE, Starościak BJ, et al. Synthesis and antibacterial activity of adamantyl substituted pyrimidines. Acta Pol Pharm. 2004;61:455–60.

  • 133.

    Farooq O, Marcelli M, Prakash GKS, Olah GA. Electrophilic reactions at single bonds. 22. Superacid-catalyzed electrophilic formylation of adamantane with carbon monoxide competing with Koch-Haaf carboxylation. J Am Chem Soc. 1988;110:864–7.

  • 134.

    Kraus GA, Siclovan TM. Bridgehead intermediates in organic synthesis. A reproducible synthesis of adamantane-containing compounds. J Org Chem. 1994;59:922.

  • 135.

    Mancuso AJ, Swern D. Activated dimethyl sulfoxide: useful reagents for synthesis. Synthesis. 1981;3:165–85.

  • 136.

    Orzeszko B, Fedoryński M, Laudy AE, Starościak BJ, Orzeszko A. Synthesis and antibacterial activity of 5-adamantan-1-yl-methyl analogues of trimethoprim. Acta Pol Pharm. 2006;63:374–7.

  • 137.

    Pelphrey PM, Popov VM, Joska TM, et al. Highly efficient ligands for dihydrofolate reductase from Cryptosporidium hominis and Toxoplasma gondii inspired by structural analysis. J Med Chem. 2007;50:940–50.

  • 138.

    Liu J, Bolstad D, Smith A, et al. Structure-guided development of efficacious antifungal agents targeting Candida glabrata dihydrofolate reductase. Chem Biol. 2008;15:990–6.

  • 139.

    Liu J, Bolstad D, Smith A, et al. Probing the active site of Candida glabrata dihydrofolate reductase with high-resolution crystal structures and the synthesis of new inhibitors. Chem Biol Drug Des. 2009;73:62–74.

  • 140.

    Kuyper LF, Roth B, Baccanari DP, et al. Receptor-based design of dihydrofolate reductase inhibitors: comparison of crystallographically determined enzyme binding with enzyme affinity in a series of carboxy-substituted trimethoprim analogues. J Med Chem. 1985;28:303–11.

  • 141.

    Cody V, Pace J, Chisum K, Rosowsky A. New insights into DHFR interactions: analysis of Pneumocystis carinii and mouse DHFR complexes with NADPH and two highly potent trimethoprim derivatives. Proteins. 2006;65:959–69.

  • 142.

    Birdsall B, Feeney J, Pascual C, et al. A 1H NMR study of the interactions and conformations of rationally designed brodimoprim analogues in complexes with Lactobacillus casei dihydrofolate reductase. J Med Chem. 1984;27:1672–6.

  • 143.

    Morgan WD, Birdsall B, Polshalov VL, Sali D, Kompis I, Feeney L. Solution structure of a brodimoprim analogue in its complex with Lactobacillus casei dihydrofolate reductase. Biochemistry. 1995;34:11690–702.

  • 144.

    Lombardo MN, G-Dayanandan N, Wright DL, Anderson AC. Crystal structures of trimethoprim-resistant DfrA1 rationalize potent inhibition by propargyl-linked antifolates. ACS Infect Dis. 2016;2:149–56.

  • 145.

    Beierlein JM, Frey KM, Bolstad DB, et al. Synthetic and crystallographic studies of a new inhibitor series targeting Bacillus anthracis dihydrofolate reductase. J Med Chem. 2008;51:7532–40.

  • 146.

    Hajian B, Scocchera E, Keshipeddy S, et al. Propargyl-linked antifolates are potent inhibitors of drug-sensitive and drug-resistant Mycobacterium tuberculosis. PLoS ONE. 2016;11:e0161740.

  • 147.

    Bush K, Leal J, Fathima S, et al. The molecular epidemiology of incident methicillin-resistant Staphylococcus aureus cases among hospitalized patients in Alberta, Canada: a retrospective cohort study. Antimicrob Resist Infect Control. 2015;14:35.

  • 148.

    Frey KM, Lombardo MN, Wright DL, Anderson AC. Towards the understanding of resistance mechanisms in clinically isolated trimethoprim-resistant, methicillin-resistant Staphylococcus aureus dihydrofolate reductase. J Struct Biol. 2010;170:93–7.

  • 149.

    Frey KM, Georgiev I, Donald BR, Anderson AC. Predicting resistance mutations using protein design algorithms. Proc Natl Acad Sci USA. 2010;107:13707–12.

  • 150.

    Frey KM, Liu J, Lombardo MN, Bolstad DB, Wright DL, Anderson AC. Crystal structures of wild-type and mutant methicillin-resistant Staphylococcus aureus dihydrofolate reductase reveal an alternate conformation of NADPH that may be linked to trimethoprim resistance. J Mol Biol. 2009;387:1298–308.

  • 151.

    Viswanathan K, Frey KM, Scocchera EW, et al. Toward new therapeutics for skin and soft tissue infections: propargyl-linked antifolates are potent inhibitors of MRSA and Streptococcus pyogenes. PLoS ONE. 2012;7:e29434.

  • 152.

    Lamb KM, Lombardo MN, Alverson J, Priestley ND, Wright DL, Anderson AC. Crystal structures of Klebsiella pneumoniae dihydrofolate reductase bound to propargyl-linked antifolates reveal features for potency and selectivity. Antimicrob Agents Chemother. 2014;58:7484–91.

  • 153.

    Scocchera E, Reeve SM, Keshipeddy S, et al. Charged nonclassical antifolates with activity against Gram-positive and Gram-negative pathogens. ACS Med Chem Lett. 2016;7:692–6.

  • 154.

    Reeve SM, Scocchera EW, G-Dayanadan N, et al. MRSA Isolates from United States hospitals carry dfrG and dfrK resistance genes and succumb to propargyl-linked antifolates. Cell Chem Biol. 2016;23:1458–67.

  • 155.

    Reeve SM, Scocchera E, Ferreira JJ, et al. Charged propargyl-linked antifolates reveal mechanisms of antifolate resistance and inhibit trimethoprim-resistant MRSA strains possessing clinically relevant mutations. J Med Chem. 2016;59:6493–500.

  • 156.

    Dale G, Broger C, D’Arcy A, Hartman P, DeHoogt R, Jolidon S, et al. A single amino acid substitution in Staphylococcus aureus dihydrofolate reductase determines trimethoprim resistance. J Mol Biol. 1997;266:23–30.

  • 157.

    Keshipeddy S, Reeve SM, Anderson AC, Wright DL. Nonracemic antifolates stereoselectively recruit alternate cofactors and overcome resistance in S. aureus. J Am Chem Soc. 2015;137:8983–90.

  • 158.

    Tobias AM, Toska D, Lange K, et al. Expression, purification, and inhibition profile of dihydrofolate reductase from the filarial nematode Wuchereria bancrofti. PLoS ONE. 2018;13:e0197173 https://doi.org/10.1371/journal.pone.0197173.

  • 159.

    Gilbert IH. Inhibitors of dihydrofolate reductase in Leishmania and trypanosomes. Biochim Biophys Acta. 2002;62126:249–57.

  • 160.

    Chowdhury SF, Guerrero RH, Brun R, Ruiz-Perez LM, et al. Synthesis and testing of 5-benzyl-2,4-diaminopyrimidines as potential inhibitors of Leishmanial and Trypanosomal dihydrofolate reductase. J Enzym Inhib. 2002;17:293–302.

  • 161.

    Sirawaraporn WR, Sertsrivanich RG, Booth C, Hansch RA, et al. Selective inhibition of Leishmania dihydrofolate reductase and Leishmania growth by 5-benzyl-2,4-diaminopyrimidines. Mol Biochem Parasitol. 1988; 31:79–85.

  • 162.

    Chan DCM, Anderson AC. Towards species-specific antifolates. Curr Med Chem. 2006;13:377–98.

  • 163.

    Borst P, Ouellette M. New mechanisms of drug resistance in parasitic protozoa. Annu Rev Microbiol. 1995;49:427–60.

  • 164.

    Foye WO, Lemke TL, Williams DA. Principles of Medicinal Chemistry. 4th ed. Media, PA: Williams and Wilkins; 2005.

  • 165.

    El-Gazzar YI, Georgey HH, El-Messery SM, et al. Synthesis, biological evaluation and molecular modeling study of new (1,2,4-triazole or 1,3,4-thiadiazole)-methylthio-derivatives of quinazolin-4(3H)-one as DHFR inhibitors. Bioorg Chem. 2017;72:282–92.

  • 166.

    Berman EM, Werbel LM. The renewed potential for folate antagonists in contemporary cancer chemotherapy. J Med Chem. 1991;34:479–85.

  • 167.

    Kisliuk RL. Folate Biochemistry in Relation to Antifolate Selectivity. In: Jackman AL, editors. Antifolate drugs in cancer therapy. cancer drug discovery and development. Totowa, NJ: Humana Press; 1999. p. 13–36.

  • 168.

    Zhang Q, Nguyen T, Mcmichael M, et al. New small-molecule inhibitors of dihydrofolate reductase inhibit Streptococcus mutans. Int J Antimicrob Agents. 2015;46:174–82.

  • 169.

    Yuthavong Y, Tarnchompoo B, Vilaivan T, et al. Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target. PNAS. 2012;109:16823–8.

  • 170.

    Then RL. Antimicrobial dihydrofolate reductase inhibitors-achievements and future options. Rev J Chemother. 2004;16:3–12.

  • 171.

    Snapka RM, Ge S, Trask J, et al. Unbalanced growth in mouse cells with amplified dhfr genes. Cell Prolif. 1997;30:385–99.

  • 172.

    Kubbies M, Stockinger H. Cell cycle-dependent DHFR and t-PA production in cotransfected, MTX-amplified CHO cells revealed by dual-laser flow cytometry. Exp Cell Res. 1990;188:267–71.

  • 173.

    Neradil J, Pavlasova G, Veselska R. New mechanisms for an old drug; DHFR- and non-DHFR-mediated effects of methotrexate in cancer cells. Klin Onkol. 2012;25:87–92.

  • 174.

    Rodríguez M, Coma S, Noé V. Development and effects of immunoliposomes carrying an antisense oligonucleotide against DHFR RNA and directed toward human breast cancer cells overexpressing HER2. Antisense Nucleic Acid Drug Dev. 2002;12:311–25.

  • 175.

    Giletti A, Esperon P. Genetic markers in methotrexate treatments. Pharmacogn J. 2018;18:689–703.

  • 176.

    Gangjee A, Li W, Kisliuk R, et al. Design, synthesis, and X-ray crystal structure of classical and nonclassical 2-amino-4-oxo-5-substituted-6-ethylthieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors and as potential antitumor agents. J Med Chem. 2009;52:4892–902.

  • 177.

    Wright DL, Anderson AC. Antifolate agents: a patent review (2006–10). Expert Opin Ther Pat. 2011;21:1293–308.

  • 178.

    Singh P, Kaur M, Sachdeva S. Mechanism inspired the development of rationally designed dihydrofolate reductase inhibitors as anticancer agents. J Med Chem. 2012;55:6381–90.

  • 179.

    Algul O, Paulsen JL, Anderson AC. 2,4-Diamino-5-(2’-arylpropargyl)pyrimidine derivatives as new nonclassical antifolates for human dihydrofolate reductase inhibition. J Mol Graph Model. 2011;29:608–13.

  • 180.

    Wróbel A, Drozdowska D Synthesis and some biological properties of new trimethoprim analogues [abstract P290]. In: Proceedings of the 7th edition of the EFMC International Symposium on Advances in Synthetic and Medicinal Chemistry (EFMC-ASMC’17). Vienna (Austria) 2017.

  • 181.

    Wróbel A, Drozdowska D Solid-phase synthesis of thirteen trimethoprim analogues as DNA-binding agents. [abstract P56]. In: 25th Young Research Fellows Meeting. France (Orléans) 2018.

  • 182.

    Bailly C, Chaires JB, Sequence-specific DNA. minor groove binders. Design and synthesis of netropsin and distamycin analouges. Bioconjugate Chem. 1999;9:513–38.

  • 183.

    Viegas-Junior C, Danuello A, da Silva BV, Barreiro EJ, Fraga CA. Molecular hybridization: a useful tool in the design of new drug prototypes. Curr Med Chem. 2007;14:1829–52.

  • 184.

    Morphy R, Rankovic Z. Designed multiple ligands. an emerging drug discovery paradigm. J Med Chem. 2005;48:6523–43.

  • 185.

    Espinoza-Fonseca LM. The benefits of the multi-target approach in drug design and discovery. Bioorg Med Chem. 2006;14:896–7.

  • 186.

    O’Boyle NM, Meegan MJ. Designed multiple ligands for cancer therapy. Curr Med Chem. 2011;18:4722–37.

  • 187.

    Rao AS, Road K. A study on dihydrofolate reductase and its inhibitors: a review. Int J. 2013;4:2535–47.

  • 188.

    Lin JT, Mbewe B, Taylor SM, et al. Increased prevalence of dhfr and dhps mutants at delivery in Malawian pregnant women receiving intermittent preventive treatment for malaria. Trop Med Int Health. 2013;18:175–8.

  • 189.

    Rana RM, Rampogu S, Zeb A, et al. In silico study probes potential inhibitors of human dihydrofolate reductase for cancer therapeutics. J Clin Med. 2019;8:233.

  • 190.

    Shah K, Lin X, Queener SF, et al. Targeting species-specific amino acid residues: design, synthesis and biological evaluation of 6-substituted pyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors and potential anti-opportunistic infection agents. Bioorg Med Chem. 2018;26:2640–50.

  • 191.

    Ouyang Y, Yang H, Zhang P, et al. Synthesis of 2,4-diaminopyrimidine core-based derivatives and biological evaluation of their anti-tubercular actives. Molecules. 2017;22:1592–619.

  • 192.

    Thakkar SS, Thakor P, Ray A. Benzothiazole analogues: Synthesis, characterization, MO calculations with PMG6 and DFT, in silico studies and in vitro antimalarial as DHFR inhibitors and antimicrobial actives. Bioorg Med Chem. 2017;25:5396–406.

  • Source