Dihydrofolate Reductase Inhibitors, Nitroheterocycles (Furans), and 8-Hydroxyquinolines

P. Veyssier; A. Bryskier

doi:10.1128/9781555815929.ch35

Chapter 35 : Dihydrofolate Reductase Inhibitors, Nitroheterocycles (Furans), and 8-Hydroxyquinolines

Authors: P. Veyssier, A. Bryskier

Content Type: Reference

Publication Year: 2005

Category: Bacterial Pathogenesis

Book DOI: 10.1128/9781555815929

Chapter DOI: 10.1128/9781555815929.ch35

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Abstract:

This chapter talks about dihydrofolate reductase inhibitors (DHFR), nitroheterocycles (furans), and 8-hydroxyquinolines. Trimethoprim and brodimoprim contain two nitrogen atoms on the pyrimidine ring which are easily protonable according to the pH of environment. Co-trimoxazole is one of the main antibacterial agents for the treatment of uncomplicated cystitis. Pharmacology studies show that the combination of compounds does not modify their behavior and that if co-trimoxazole is compared with the other combinations an advantage may be found for trimethoprim-sulfadiazine in urinary tract infections and renal insufficiency. Many 6-6 fused rings have been prepared with the aim of increasing the selectivity for T. gondii and P. carinii DHFR. A series of hybrids was synthesized. Within this series one analog was 500-fold more potent than trimethoprim against P. carinii and T. gondii and displayed an excellent selectivity. The combination of epiroprim and dapsone is highly effective against P. carinii pneumonia in rats and T. gondii infection in mice. In vitro, the sulfones are active against T. gondii, particularly dapsone. In murine P. carinii pneumocystosis, dapsone is effective in treatment and prevention. In humans, the combination trimethoprim-dapsone in curative treatment and dapsone alone in preventive treatment are effective. Like the sulfonamides, the sulfones interfere with folate synthesis. They also have a potent antioxidant action. Lastly, dapsone inhibits the transport of adenosine through the erythrocyte wall and prevents its incorporation in the nucleic acid of plasmodia and probably toxoplasmas and P. carinii.

Citation: Veyssier P, Bryskier A. 2005. Dihydrofolate Reductase Inhibitors, Nitroheterocycles (Furans), and 8-Hydroxyquinolines, p 941-963. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch35

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Dihydrofolate Reductase Inhibitors, Nitroheterocycles (Furans), and 8-Hydroxyquinolines

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Figure 1

Sulfonamides for systemic use

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Figure 1

Sulfonamides for systemic use

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Figure 2

Sulfonamides for intestinal use

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Figure 2

Sulfonamides for intestinal use

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Figure 3

N 4-acetylation of sulfonamides. Acetyl CoA, acetyl coenzyme A

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Figure 3

N 4-acetylation of sulfonamides. Acetyl CoA, acetyl coenzyme A

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Figure 4

Pyrimidine and pyridine sulfonamides: structures of hydroxy metabolites

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Figure 4

Pyrimidine and pyridine sulfonamides: structures of hydroxy metabolites

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Figure 5

2, 5-Diaminopyrimidine derivatives

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Figure 5

2, 5-Diaminopyrimidine derivatives

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Figure 6

Protonation and deprotonation of trimethoprim

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Figure 6

Protonation and deprotonation of trimethoprim

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Figure 7

Reduction to tetrahydrofolate

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Figure 7

Reduction to tetrahydrofolate

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Figure 8

Mode of action of trimethoprim

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Figure 8

Mode of action of trimethoprim

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Figure 9

Role of tetrahydrofolates and sites of action of sulfonamides and benzylpyrimidines

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Figure 9

Role of tetrahydrofolates and sites of action of sulfonamides and benzylpyrimidines

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Figure 10

Mode of action of 2,4-diaminopyrimidines

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Figure 10

Mode of action of 2,4-diaminopyrimidines

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Figure 11

Thymidylate activity

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Figure 11

Thymidylate activity

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Figure 12

Degradation products of trimethoprim

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Figure 12

Degradation products of trimethoprim

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Figure 13

2,4-Diaminobenzylpyrimidines with antiparasitic activities

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Figure 13

2,4-Diaminobenzylpyrimidines with antiparasitic activities

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Figure 14

Iclaprim

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Figure 14

Iclaprim

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Figure 15

Enantiomers of AR-101

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Figure 15

Enantiomers of AR-101

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Figure 16

Compound A. TMP, trimethoprim

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Figure 16

Compound A. TMP, trimethoprim

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Figure 17

Sulfones

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Figure 17

Sulfones

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Figure 18

Nitroheterocycle furans

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Figure 18

Nitroheterocycle furans

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Figure 19

8-Hydroxyquinoline derivatives

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Figure 19

8-Hydroxyquinoline derivatives

References

/content/book/10.1128/9781555815929.ch35

1. Bryskier A, 1983, Les inhibiteurs de la dihydrofolate réductase—classification et relation structure activité, p 19- 36, in Modai J, ed, Triméthoprime et sulfamides, Soc Pathol Infect Langue Fse.

2. Chauvin P,, Cnudde F,, Leynadier F,, Halpern GM,, Dry J, 1991, Aspects physiopathologiques des réactions d’intolérance aux sulfamides au cours du SIDA, Med Hyg 49, 1013– 1024.

3. Fegueux S,, de Truchis P,, Balloul H,, Maslo C,, Matheron S,, Coulaud JP, 1990, Réintroduction de la sulfadiazine au cours du SIDA, Presse Med 19, 1947.

4. Fischl MA,, Dickinson GM, La, Voie L, 1988, Safety and efficacy of sulfamethoxazole and trimethoprim chemoprophylaxis for Pneumocystis carinii pneumonia in AIDS, JAMA, 259, 1185– 1189.

5. Fox BC,, Sollinger HW,, Belzer FO,, Maki DG, 1990, A prospective randomized double blind study of TS for prophylaxis of infection in renal transplantation: clinical efficacy, absorption of TS, effects on the microflora and the cost benefits of prophylaxis, Am J Med, 89, 255– 274.

6. Glatt AE,, Chirgwin K,, Landesman SH, 1988, Current concepts: treatment of infections associated with human immunodeficiency virus, N Engl J Med, 319, 1439– 1448.

7. Hughes WT, 1988, Trimethoprim and sulfonamides, p 229– 237, in Peterson PK,, Verhoef J, ed, Antimicrobial Agents Annual III, Elsevier Science Publishers BV.

8. Hughes WT,, Killmar JT, 1991, Synergistic anti-pneumocystis carinii effects of erythromycin and sulfisoxazole, J Acquir Immune Defic Syndr, 4, 532– 537.

9. Hutabarat RM,, Unadkat JD,, Sahajwalla C,, McNamara S,, Ramsey B,, Smith AL, 1991, Disposition of drugs in cystic fibrosis. Sulfamethoxazole and trimethoprim, Clin Pharmacol Ther, 49, 402– 409.

10. Kucers A,, Bennet N, 1979, Trimethoprim sulfamethoxazole, p 687– 729, in Use of Antibiotics, W Heinemann, London.

11. La pneumocystose au cours de l’infection HIV, 1990, Conference de consensus 1990, Med Mal Infect, 20 (n° special), 320– 324.

12. Masur H,, Kovacs JA, 1988, Treatment and prophylaxis of pneumocystis carinii pneumoniae, p 181– 191, in Sande MA,, Volberding PA, ed, Medical Management of AIDS, WB Saunders Co, Philadelphia.

13. Pang LW,, Limsomwong N,, Snigharaj P,, Canfield CJ, 1989, Malaria prophylaxis with proguanil and sulfisoxazole in children living in a malaria endemic area, 671, 51– 58.

14. Remington JS,, Luft BJ, 1988, Drugs used in the treatment of toxoplasmosis, p 327– 336, in Peterson PK,, Verhoef J, ed, Antimicrob Agents Annual III, Elsevier Science Publishers BV.

15. Saimot AG,, Girard PM, 1990 Interactions des traitements anti-viraux et antiparasitaires, p 141– 152, in Journees de reanimation de l’hopital Claude Bernard, Arnette, Paris.

16. White MW,, Haddad ZH,, Brunner E,, Sainz C, 1989, Desensitization to TS in patients with acquired deficiency and pneumocystis carinii pneumonia, Ann Allergy, 62, 177– 179.

17. Wolff M, 1990, Posologie des médicaments antiparasitaires chez l’adulte en insuffisance rénale, p 153– 161, in Journees de reanimation de l’hopital Claude Bernard, Arnette, Paris.

18. Biggs JT,, Uher AK,, Levy L,, Gordon GR,, Peters JH, 1975, Renal and biliary dispositions of dapsone in the dog, Antimicrob Agents Chemother, 7, 816– 824.

19. Bryskier A,, Labro MT, 1989, Les antifolates—classification, relation structure-activité, propriétés biologiques, p 69– 100, in Paludisme et Medicaments, Arnette, Paris.

20. Medina L,, Mills J,, Leoung G,, Hopewell PC,, Lee B,, Modin G,, Benowitz N,, Wofsy CB, 1990, Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone, N Engl J Med, 323, 776– 782.

21. Stone OJ, 1990, Sulfapyridine and sulfones decrease glycosaminoglycans viscosity in dermatitis herpetiformis, ulcerative colitis, and pyoderma gangrenosum, Med Hypotheses, 31, 99– 103.

22. Wordell CJ,, Hauptman SP, 1988, Treatment of pneumocystis pneumonia in patients with AIDS, Clin Pharm, 7, 514– 527.

23. Wozel G, 1989, The story of sulfones in tropical medicine and dermatology, Int J Dermatol, 28, 17– 21.

24. Conklin JD, 1978, The pharmacokinetics of nitrofurantoin and its related bioavailability, Antibiot Chemother, 25, 233– 252.

25. Holmberg L,, Boman G,, Bottiger LE,, Eriksson B,, Spross R,, Wessling A, 1980, Adverse reactions to nitrofurantoin, analysis of 921 reports, Am J Med, 69, 5, 733– 738.

26. Veyssier P,, Bryskier A, 1985, Agents antibactériens de synthèse, Enc Med Chir Thérapeutique, 25016 D-10.

27. Hannedouche T,, Godin M,, Fillastre JP, 1983, Les effets secondaires des medicaments utilisés pour le traitement des infections urinaires, Therapie, 38, 281– 293.

28. Lambert Zechovsky N,, Leveque B,, Bingen E,, Pillion G,, Chapelle J,, Mathieu H, 1987, Activité clinique et effet de la nitroxoline sur la flore fécale chez l’enfant, Pathol Biol, 35, 669– 672.

Tables

Dihydrofolate Reductase Inhibitors, Nitroheterocycles (Furans), and 8-Hydroxyquinolines

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Table 1

Pharmacokinetics of sulfonamides

Table 1

Pharmacokinetics of sulfonamides

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Table 2

Solubilities of sulfonamides at 25ºC

Table 2

Solubilities of sulfonamides at 25ºC

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Table 3

Half-lives of sulfonamides in children

Table 3

Half-lives of sulfonamides in children

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Table 4

Tissue diffusion of sulfonamides and trimethoprim

Table 4

Tissue diffusion of sulfonamides and trimethoprim

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Table 5

Percentage of the sulfonamide administered dose eliminated unchanged or as metabolites in urine

Table 5

Percentage of the sulfonamide administered dose eliminated unchanged or as metabolites in urine

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Table 6

Affinity for DHFR

Table 6

Affinity for DHFR

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Table 7

ThyX and FolA gene distribution

Table 7

ThyX and FolA gene distribution

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Table 8

Physicochemical properties of 2,4-diaminopyrimidines

Table 8

Physicochemical properties of 2,4-diaminopyrimidines

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Table 9

In vitro activities of trimethoprim and brodimoprim against gram-positive cocci

Table 9

In vitro activities of trimethoprim and brodimoprim against gram-positive cocci

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Table 10

In vitro activities of benzylpyrimidines against gram-negative bacilli

Table 10

In vitro activities of benzylpyrimidines against gram-negative bacilli

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Table 11

In vitro activity against S. maltophilia

Table 11

In vitro activity against S. maltophilia

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Table 12

Breakpoints (French Committee for Antibiotic Susceptibility Testing)

Table 12

Breakpoints (French Committee for Antibiotic Susceptibility Testing)

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Table 13

Prevalence of co-trimoxazole resistance

Table 13

Prevalence of co-trimoxazole resistance

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Table 14

Prevalence of resistance of E. coli in urinary tract infections in France

Table 14

Prevalence of resistance of E. coli in urinary tract infections in France

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Table 15

In vitro activities of trimethoprim and co-trimoxazole

Table 15

In vitro activities of trimethoprim and co-trimoxazole

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Table 16

Comparative in vitro activities of trimethoprim and tetroxoprim

Table 16

Comparative in vitro activities of trimethoprim and tetroxoprim

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Table 17

Affinities for DHFR of trimethoprim and piritrexin

Table 17

Affinities for DHFR of trimethoprim and piritrexin

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Table 18

Pharmacokinetic characteristics of the different benzylpyrimidine derivatives

Table 18

Pharmacokinetic characteristics of the different benzylpyrimidine derivatives

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Table 19

In vitro activity of iclaprim

Table 19

In vitro activity of iclaprim

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Table 20

Affinity for DHFR of gram-positive cocci

Table 20

Affinity for DHFR of gram-positive cocci

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Table 21

Preliminary pharmacokinetics of iclaprim

Table 21

Preliminary pharmacokinetics of iclaprim

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Table 22

Proprietary names of combinations

Table 22

Proprietary names of combinations

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Table 23

Plasma protein binding

Table 23

Plasma protein binding

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Table 24

Penetration in bronchial secretions

Table 24

Penetration in bronchial secretions

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Table 25

Trimethoprim distribution in blister fluid

Table 25

Trimethoprim distribution in blister fluid

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Table 26

2,4-Diaminopyrimidine systems for parasites

Table 26

2,4-Diaminopyrimidine systems for parasites

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Table 27

In vitro activity of epiroprim

Table 27

In vitro activity of epiroprim

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Table 28

In vitro activity of epiroprim against mycobacteria

Table 28

In vitro activity of epiroprim against mycobacteria

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Table 29

In vivo efficacy of epiroprim

Table 29

In vivo efficacy of epiroprim

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Table 30

Physicochemical properties of sulfones

Table 30

Physicochemical properties of sulfones

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Table 31

Dapsone slow and rapid acetylators (100-mg single oral dose to nine patients)

Table 31

Dapsone slow and rapid acetylators (100-mg single oral dose to nine patients)