3.5 Reported Classes of Compounds for PfDHODH
Inhibition
There are nine chemical classes of PfDHODH inhibitors known in the literature
(Fig. 10). Different classes of PfDHODH reported in the literature are triazolopyrimidine (I) [78], diethyl 2-((arylamino)methylene)malonate (II) [79], benzamide/
naphthamide derivatives of anthranilic acid (III) [56], N-alkyl-5-benzimidazole
thiophene-2-carboxamide (IV) [65, 80], benzamide (V) [55], N-substituted salicylamides (VI) [81], thiazole (VII) [82],7-arylaminopyrazolo[1,5-a]pyrimidines
(VIII) [83], and dihydrothiophenone (IX) [84]. DSM265 [69] from triazolopyrimidine class is in clinical development phase, and two analogs of Genz-667348
(N-alkyl-5-benzimidazole thiophene-2-carboxamide derivatives) [80b] are undergoing pilot toxicity testing to determine their suitability as clinical development
candidates.
3.6 Structure-Based Drug Design of PfDHODH inhibitors
All the early efforts to the identified PfDHODH inhibitors are based on the known
HsDHODH inhibitors. First effort was initiated by Boa et al. (in 2005), in which
various analogues of Brequinar (Fig. 11 XII) (HsDHODH inhibitor; immunosuppressive agent) were designed using analog-based methods [54]. These
quinolone-4-carboxylic acid derivatives showed poor to moderate selectivity and
activity in medium micromolar range. This study was followed by report of
high-throughput screening studies on PfDHODH inhibitors by Baldwin et al.
(2005) [55]. The chemical classes included halogenated phenyl benzamide/
naphthamides and napthyl or quinolinyl substituted urea-based compounds.
Inhibitor binding site was confirmed by direct site mutagenesis (His185Ala and
Fig. 10 Different classes of PfDHODH inhibitors
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Inhibition
There are nine chemical classes of PfDHODH inhibitors known in the literature
(Fig. 10). Different classes of PfDHODH reported in the literature are triazolopyrimidine (I) [78], diethyl 2-((arylamino)methylene)malonate (II) [79], benzamide/
naphthamide derivatives of anthranilic acid (III) [56], N-alkyl-5-benzimidazole
thiophene-2-carboxamide (IV) [65, 80], benzamide (V) [55], N-substituted salicylamides (VI) [81], thiazole (VII) [82],7-arylaminopyrazolo[1,5-a]pyrimidines
(VIII) [83], and dihydrothiophenone (IX) [84]. DSM265 [69] from triazolopyrimidine class is in clinical development phase, and two analogs of Genz-667348
(N-alkyl-5-benzimidazole thiophene-2-carboxamide derivatives) [80b] are undergoing pilot toxicity testing to determine their suitability as clinical development
candidates.
3.6 Structure-Based Drug Design of PfDHODH inhibitors
All the early efforts to the identified PfDHODH inhibitors are based on the known
HsDHODH inhibitors. First effort was initiated by Boa et al. (in 2005), in which
various analogues of Brequinar (Fig. 11 XII) (HsDHODH inhibitor; immunosuppressive agent) were designed using analog-based methods [54]. These
quinolone-4-carboxylic acid derivatives showed poor to moderate selectivity and
activity in medium micromolar range. This study was followed by report of
high-throughput screening studies on PfDHODH inhibitors by Baldwin et al.
(2005) [55]. The chemical classes included halogenated phenyl benzamide/
naphthamides and napthyl or quinolinyl substituted urea-based compounds.
Inhibitor binding site was confirmed by direct site mutagenesis (His185Ala and
Fig. 10 Different classes of PfDHODH inhibitors
198
S. Bhagat et al.