Structural studies on bioactive compounds. Part 36: design, synthesis and biological evaluation of pyrimethamine-based antifolates against Pneumocystis carinii.

As part of a research effort to improve the quality of current chemotherapy of Pneumocystis carinii pneumonia, we report a structure-based design project to optimise activity, species selectivity and pharmaceutical properties of the triazenyl-pyrimethamine TAB (4) (IC(50)=0.17 microM; rat liver DHFR IC(50)/P. carinii DHFR IC(50)=114). This has led us to design, synthesise and evaluate four new series of pyrimethamine derivatives bearing triazole, triazolium, triazinium and amino moieties at the 3'-position of the p-chlorophenyl ring. Such stabilised 'triazene' derivatives address the potentially compromised pharmaceutical profile of TAB and the 3'-amine substituted agents afford conformationally flexible substitutes. The benzylamino-pyrimethamine derivative (24a) (IC(50)=0.12 microM, rat liver DHFR IC(50)/P. carinii DHFR IC(50): 5.26) was the most potent and the only P. carinii-selective antifolate of the new series.

[1]  P. Kollman,et al.  A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules , 1995 .

[2]  P K Bryant,et al.  The structure of Pneumocystis carinii dihydrofolate reductase to 1.9 A resolution. , 1994, Structure.

[3]  M. Stevens,et al.  Structural studies on bioactive compounds. 28. Selective activity of triazenyl-substituted pyrimethamine derivatives against Pneumocystis carinii dihydrofolate reductase. , 1997, Journal of Medicinal Chemistry.

[4]  Y. Shealy.  Syntheses and biological activity of 5-aminoimidazoles and 5-triazenoimidazoles. , 1970, Journal of pharmaceutical sciences.

[5]  T. A. Connors,et al.  Tumour inhibitory triazenes: structural requirements for an active metabolite. , 1976, Biochemical pharmacology.

[6]  E. Bliss,et al.  Structural studies on bio-active compounds. Part 5. Synthesis and properties of 2,4-diaminopyrimidine dihydrofolate reductase inhibitors bearing lipophilic azido groups , 1987 .

[7]  A. Gescher,et al.  The metabolism of triazene antitumor drugs. , 1987, Pharmacology & therapeutics.

[8]  A. Padwa,et al.  Dipolar cycloaddition reaction of diazoalkanes with trimethylsilyl substituted alkynes. Steric control of regiochemistry by the trimethylsilyl group , 1990 .

[9]  S F Queener,et al.  Pneumocystis carinii dihydrofolate reductase used to screen potential antipneumocystis drugs , 1991, Antimicrobial Agents and Chemotherapy.

[10]  Y. Kondo,et al.  Synthesis and Reaction of 1-Phenyl-4-trimethykstannyl-1,2,3-triazoles , 1993 .

[11]  S F Queener,et al.  Identification of highly potent and selective inhibitors of Toxoplasma gondii dihydrofolate reductase , 1993, Antimicrobial Agents and Chemotherapy.

[12]  M. Stevens,et al.  Antitumor imidazotetrazines. 32. Synthesis of novel imidazotetrazinones and related bicyclic heterocycles to probe the mode of action of the antitumor drug temozolomide. , 1995, Journal of medicinal chemistry.

[13]  V. Cody,et al.  Structural studies on bioactive compounds. 30. Crystal structure and molecular modeling studies on the Pneumocystis carinii dihydrofolate reductase cofactor complex with TAB, a highly selective antifolate. , 2000, Biochemistry.

[14]  W. Fitzgibbon,et al.  Synthesis and properties of the antileukemic agent 5(or 4)-[3,3-Bis(2-chloroethyl)-1-triazeno]imidazole-4(or 5)-carboxamide. , 1968, Journal of pharmaceutical sciences.

[15]  D C Chan,et al.  Structural studies on bioactive compounds. 34. Design, synthesis, and biological evaluation of triazenyl-substituted pyrimethamine inhibitors of Pneumocystis carinii dihydrofolate reductase. , 2001, Journal of medicinal chemistry.

[16]  M. Stevens,et al.  Antitumour polycyclic acridines. Part 3.1 A two-step conversion of 9-azidoacridine to 7H-pyrido[4,3,2-kl]acridines by Graebe–Ullmann thermolysis of substituted 9-(1,2,3-triazol-1-yl)acridines , 1998 .

[17]  M. Nasr,et al.  Identification of a class of sulfonamides highly active against dihydropteroate synthase form Toxoplasma gondii, Pneumocystis carinii, and Mycobacterium avium , 1996, Antimicrobial agents and chemotherapy.

[18]  S. Queener.  New drug developments for opportunistic infections in immunosuppressed patients: Pneumocystis carinii. , 1995, Journal of medicinal chemistry.

[19]  S. Hünig,et al.  Triazeniumsalze — eine neue Verbindungsklasse , 1979 .

[20]  Y. Shealy,et al.  Complete Inhibition of Mouse Leukaemia L1210 by 5(or 4)-[3,3-Mbis (2-Chloroethyl)-l-triazeno]imidazole-4(or 5)-carboxamide (NSC-82196) , 1966, Nature.

[21]  D. Hlasta,et al.  STERIC EFFECTS ON THE REGIOSELECTIVITY OF AN AZIDE-ALKYNE DIPOLAR CYCLOADDITION REACTION : THE SYNTHESIS OF HUMAN LEUKOCYTE ELASTASE INHIBITORS , 1994 .

[22]  P. L. Levins,et al.  Potential carcinolytic agents. IV. Diazoamino mustards. , 1966, Journal of medicinal chemistry.