Design, synthesis and evaluation of trisubstituted thiazoles targeting Plasmodium falciparum cysteine proteases

Article abstract of DOI:10.1007/s00044-005-0126-y

The Plasmodium falciparum cysteine proteases, falcipains, have been established as novel targets for antimalarial drug design. Using the de novo design approach, several trisubstituted thiazole analogs were generated as potential inhibitors of these enzymes. A general and convenient synthetic approach for these novel trisubstituted thiazoles is reported here. Substituents at the 4^th and 5^th positions of the target thiazoles were introduced by a Hantzsch reaction, and the chain at the second position was extended through a Sandmeyer reaction, formylation, and Wittig olefination. In vitro enzyme inhibition studies have identified three inhibitors (14, 16, 23) of the falcipains with one (14) showing dual activity against both falcipain-2 and falcipain-3 and IC₅₀ values of 6.6 and 29.4 μM, respectively. Birkhaeuser Boston 2005.

Full text of DOI:10.1007/s00044-005-0126-y

Med Chem Res 14:2 (2005) 74–105
௠ Birkha¨user Boston 2005

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103