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AssigneeNone recorded
InventorsKevin K. Pitzer, John P. Scovill, Dennis E. Kyle, Lucia Gerena
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Compounds, compositions and methods are provided for treating malaria parasites in vitro and in vivo by administering indolo[2,1-b]quinazoline-6,12-dione compounds of Formula I. 1 wherein A, B, C, D, E, F, G and H are independently selected from carbon and nitrogen, or A and B or C and D can be taken together to be nitrogen or sulfur, with the proviso that not more than three of A, B, C, D, E, F, G and H are other than carbon; wherein R1 through R8 are independently selected from the group consisting of, but not limited to, the halogens (F, Cl, Br, and I), alkyl groups, trifluoromethyl groups, methoxyl groups, the carboxy methyl or carboxy ethyl group (COOCH3 or COOCH2CH3), nitro, aryl, heteroaryl, cyano, amino, dialkylaminoalkyl, 1-(4-alkylpiperazinyl), and the pharmaceutically acceptable salts thereof; and wherein X is independently selected from the group consisting of any atom especially oxygen, or any side chain necessary to make the indolo[2,1-b]quinazoline-6,12-dione compound a “prodrug” as the term is understood by one of ordinary skill in the art of medicinal chemistry. In other words, a side chain having a structure where a carbon-nitrogen double bond bears substituents that make the prodrug more water soluble and bioavailable.
An antimalarial compound comprising one or more indolo[2,1-b]quinazoline-6,12-dione compounds of Formula I:
An antimalarial composition comprising a pharmaceutically effective amount of one or more indolo[2,1-b]quinazoline-6,12-dione compounds of Formula I:
A method of treating malaria in a host caused by malaria parasites comprising:
A method of inhibiting the growth of malaria in vitro comprising:
The method of 37, wherein said malaria parasites are present in Albuman I® serum or blood serum.
An antimalarial prodrug composition comprising a pharmaceutically effective amount of one or more indolo[2,1-b]quinazoline-6,12-dione compounds of Formula I:
Dependencies are inferred from the claim text.
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In which the condensed system contains three hetero rings: ortho-condensed systems
In which the condensed system contains two hetero rings: ortho-condensed systems
In which the condensed system contains three hetero rings: ortho-condensed systems
In which the condensed system contains two hetero rings: ortho-condensed systems
Term end not estimated
The present invention relates to new and existing indolo[2,1-b]quinazoline-6,12-dione derivatives which are useful in killing malaria parasites, antimalarial compositions containing the compounds, and to methods of treating malaria with the compounds and compositions, alone or in combination with other antimalarial agents both in vitro and in vivo.
The current global situation in respect to malaria has recently been detailed by Peters [W. Peters, “Drug Resistance in Malaria Parasites of Animals and Man”, Advances in Parasitology, vol. 41, pp 1-62 (1998)]. Currently, about two billion people are exposed to malaria and 400 million are infected with the disease. Between 100-200 million new cases occur each year. There are approximately 1-2 million deaths annually due to malaria. The global situation is worsening. The pertinent facts are these: very few new antimalarial drugs have been introduced in the past quarter century; there is massive pressure for the development of drug resistance due to the presence of large numbers of non-immune people in areas where malaria is efficiently transmitted; and resistance by Plasmodium falciparum and Plasmodium vivax to chloroquine is being documented in an increasingly wide geographic area.
Other frontline drugs currently used for the treatment and prevention of malaria such as mefloquine and halofantrine, are becoming increasingly ineffective. Newly introduced artemsinin analogs (artesunate and artemether), while effective for the-treatment of malaria, may be too toxic for long term administration required for prophylaxis. As a result, the idea of malaria eradication has been abandoned and replaced with the more realistic target of malaria control.
In Vitro Inhibition of Plasmodium falciparum
The in vitro assays were conducted by using a modification of the semiautomated microdilution technique of Desjardins et al.11 and Chulay et al.12 Two strains of Plasmodium falciparum clones, from CDC Indochina III (W-2), CDC Sierra Leone I (D-6). The W-2 clone is susceptible to mefloquine but resistant to chloroquine, sulfadoxine, pyrimethamine, and quinine. The D-6 clone is resistant to mefloquine but susceptible to chloroquine, sulfadoxine, pyrimethamine, and quinine. They were derived by direct visualization and micromanipulation from patient isolates.13 Test compounds were initially dissolved in DMSO and diluted 400-fold in RPMI 1640 culture medium supplemented with 25 mM Hepes, 32 mM HaHCO3, and 10% Albumax I® (GIBCO BRL, Grand Island, N.Y.). These solutions were subsequently serially diluted 2-fold with a Biomek 1000® (Beckman, Fullerton, Calif.) over 11 different concentrations. The parasites were exposed to serial dilutions of each compound for 48 h and incubated at 37° C. with 5% O2, 5% CO2, and 90% N2 prior to the addition of [3H]hypoxanthine. After a further incubation of 18 h, parasite DNA was harvested from each microtiter well using Packard Filterrnate 196 Harvester® (Meriden, Conn.) onto glass filters. Uptake of [3H]hypoxanthine was measured with a Packard Topcount scintillation counter. Concentration-response data were analyzed by a nonlinear regression logistic dose-response model, and the IC50 values (50% inhibitory concentrations) for each compound were calculated (see Table 1, values within parentheses ( )). This procedure was repeated with the test compounds initially dissolved in DMSO and diluted 400-fold in RPMI 1640 culture medium supplemented with 25 mM Hepes, 32 mM HaHCO3, and with blood serum replacing the 10% Albumax I® (see Table 1, figures without parentheses). The values without parentheses indicate culture in blood serum which more closely resemble conditions in a living animal.
Four strains of Plasmodium falciparum clones, from CDC Indochina III (W-2), CDC Sierra Leone I (D-6), Thai WR75-TM9, and Thai TM90C2B were utilized in susceptibility testing and the IC50 results appear in Table 1. 1 TABLE 1 In Vitro Antimalarial Activity. Concentration of Indolo[2,3-b]quinazoline-6,12-dione Inhibiting uptake of [3H]Hypoxanthine by Parasitized Red Blood Cells by 50% (IC50, ng/mL) Example IC50 IC50 IC50 IC50 No. Structure (W-2) (D-6) (TM90C2B) (WR75-TM9) 1. 6 (69)* (69) 2. 7 (15626) (12481) 3. 8 (>50000) (>50000) 4. 9 (2.33) 15.335* (4.07) 18.888 29.846 27.319 7.165 5. 10 (263.86) (313.106) 6. 11 (502.79) (527) 7. 12 (512.7) (576.53) 8. 13 (62) (62) 9. 14 (403) (471) 10. 15 (131) (138) 11. 16 (2.8) 14.678 (4.9) 22.068 16.383 35.991 1.587 12. 17 (1.6) 5.274 5.787 6.539 (4.9) 8.535 14.239 11.005 9.738 16.914 11.1113 11.951 16.249 19.374 13. 18 (5.1) 4.335 (14.3) 14.842 10.531 9.837 21.542 13. 19 (5.8) 10.091 (10.0) 23.258 20.119 10.499 14. 20 (5.76) (10.17) 15. 21 (81.99) (125.58) 16. 22 (1014) (2160) 17. 23 (0.84) 2.125 (1.53) 4.928 4.207 9.932 8.002 18. 24 (512.93) (812.73) 19. 25 (1.58) 8.138 (2.57) 13.523 9.784 18.937 .485 20. 26 (734.34) (1054.46) 21. 27 (0.43) 1.278 (0.93) 0.926 2.302 2.997 1.349 22. 28 (262.92) (277.72) 23. 29 (1.67) (3.97) 24. 30 (0.91) 0.912 4.638 (2.01) 10.078 7.782 17.411 8.059 25. 31 (1990.37) (1842.69) 26. 32 (609.29) (589.01) 27. 33 (1.79) 35.649 (3.01) 95.331 41.090 139.605 5.86 28. 34 (126) (19.925) (124) (38.541) 29. 35 (130.58) (149.32) 30. 36 (354.29) (499.81) 31. 37 (134.03) (160.67) 32. 38 (2588.82) (3848.62) 33. 39 (79.58) (67.06) 34. 40 (601.05) (588.27) 35. 41 (133.86) (103.44) 36. 42 (4815.61) (4204.57) 37. 43 (3483.15) (3778.15) 38. 44 (203.16) (241.86) 39. 45 (1.88) 1.870 (3.57) 3.570 46.039 4.203 40. No entry 41. 46 (7.66) (12.34) 42. 47 (63.17) (76.43) 43. 48 (23,000) (38,236) 44. 49 (5859.64) (6924.46) 45. 50 (0.728) 4.741 (1.28) 6.767 8.759 1.147 14.152 46. 51 (6.32) 22.995 (7.61) 42.612 24.417 66.441 47. No Entry 48. 52 (7.74) 58.100 (13.9) 97.106 55.796 66.666 157.162 48. 53 (508.19) (584.37) 49. 54 (74.75) (73.93) 50. 55 (11.16) (44.22) 51. 56 (8760) (8693) 52. 57 (64.69) (73.33) 53. 58 (4872.21) (9006) 54. 59 (124.03) (74.58) 55. 60 (2.1) 2.303 (7.2) 11.238 5.483 14.216 56. 61 (117) (216) 57. 62 (10.58) 28.943 (20.33) 46.492 62.233 82.551 58. 63 (2.73) 4.272 (4.52) 10.461 8.095 17.291 59. 64 (2.47) 17.707 (4.37) 37.894 24.005 50.842 1.306 60. 65 (67.86) (78.08) 61. 66 (187) (247) 62. 67 (16) (31.27) 63. 68 (1.5) 1.228 (3.16) 0.946 1.162 1.965 64. 69 (9.25) 36.831 (15.86) 70.142 38.338 38.389 65. 70 (153.98) (258.88) 66. 71 (448.53) (516.51) 67. 72 (4423.91) (4435.40) 68. 73 (3.86) 2.455 (7.86) 4.121 3.731 5.469 69. 74 (2.13) 8.494 (4.04) 12.333 10.170 23.876 70. 75 (8.69) 6.098 (13.22) 5.736 77.808 10.999 24.37 71. 76 (120.06) (143.32) 72. 77 (7465) (7860) 73. 78 (3.75) 2.855 (5.40) 4.889 4.464 10.506 74. 79 (3.52) 59.846 (2.19) 79.578 42.505 127.39 75. 80 (572.94) (534.47) 76. 81 (159.65) (223.53) 77. 82 (165.32) (220.3) 78. 83 (0.86) 0.935 (0.93) 1.966 1.764 3.297 79. 84 (68.76) (69.96) 80. 85 (6902.53) (7965.51) 81. 86 (73.92) (110.16) 82. 87 (124) (62.82) 83. 88 (1.8) 7.186 (3.11) 15.141 12.864 25.717 84. 89 (937.57) (1710.33) 85. 90 (105.36) (135.96) 86. 91 (2.3) 1.908 (3.6) 3.63 2.079 35.678 4.506 87. 92 (3.51) 1.252 (4.92) 2.310 0.696 4.438 88. 93 (177.45) (490.16) 89. 94 (68.77) (111.69) 90. 95 (3.93) 15.601 (7.59) 16.320 6.145 30.045 91. 96 (1.8) 5.521 4.977 (0.24) 9.064 10.137 9.825 4.594 9.941 5.438 4.449 9.941 16.412 *Values in parenthesis represent assays conducted in Albumax. **Values without parenthesis represent assays conducted in blood plasma.