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  • The possibility that a carboxyl group attached to the


    The possibility that a carboxyl group attached to the or position of an -arylaminomethylenemalonate ester would lead to increased selectivity for DHODH has been tested and found not to be the case. Indeed, reduced selectivity compared with the corresponding ester is observed and is attributed to a ‘reversed’ binding mode in which the dominant interaction is a salt bridge to arginine in both species. Lack of activity observed for variants with a head group derived from Meldrum’s enkephalin combined with docking studies suggest that a diester head group binds in a conformation where the alkyl chains of the two ester groups are oriented in opposite directions. Acknowledgements The authors gratefully acknowledge the financial support provided by UK Engineering and Physical Sciences Research Council (studentship to D.C.) and to the Biotechnology and Biological Sciences Research Council (studentship to P.B.)
    Introduction Malaria is one of the world\'s “biggest three infectious diseases” (HIV/AIDS, tuberculosis, and malaria) that kill millions of people every year. Effective vaccines have not been developed; thus, chemotherapy remains the mainstay of prevention and treatment. Unfortunately, drug resistance to almost every known antimalarial agent has compromised the effectiveness of control programs: the antimalarial drugs reported so far effectively worked only for certain periods of time until resistance was developed [1]. This justified the search for new approaches for the pharmacological treatment of malaria [2]. One of these approaches was found to be the targeting of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH), an enzyme involved in the catalysis of the fourth step in de novo pyrimidine biosynthesis. [3,4] The de novo pyrimidine biosynthesis pathway is crucial to the survival of the parasite: unlike human cells, which are able to utilize the salvage pathway for pyrimidine acquisition, Plasmodium species can only access de novo-synthesized pyrimidines. Several scaffolds were investigated in the design of new PfDHODH inhibitors (Fig. 1) [3,4]. Among them, the triazolopyrimidine DSM265 was developed by Phillips and co-workers starting from a scaffold discovered in a high-throughput screening [5]. DSM265, a potent inhibitor of the P. falciparum and P. vivax DHODH with excellent selectivity towards the P. falciparum enzyme, as compared to human DHODH (hDHODH), is the first PfDHODH inhibitor to reach clinical development for the treatment of malaria [5]. Showing both a good safety profile and a long half-life [6], this compound reached phase 2a studies in patients with uncomplicated P. falciparum or P. vivax malaria infection [7]. During these trials, DSM265 showed single-dose efficacy for the treatment of P. falciparum malaria while lower efficacy against P. vivax. Unfortunately, recurrent parasites were found in three patients, two of which had mutations in the dhodh gene (dhodh Cys276Tyr and Cys276Phe respectively). These mutations were shown to be associated with higher EC50 values for DSM265 in in vitro resistance analysis. This fact emphasizes the need of adding PfDHODH inhibitors with different chemical scaffolds to the human pharmacopoeia. Following this aim, Phillips and co-workers presented recently PfDHODH inhibitors based on an isoxazolopyrimidine scaffold (Fig. 1) [8]. In recent years we have been focusing on targeting hDHODH [[9], [10], [11], [12]]. By improving the strategy of scaffold hopping to replace the acidic moieties by acidic hydroxylated azoles in the biologically active lead brequinar, we successfully designed a new class of hDHODH inhibitors [[13], [14], [15], [16], [17]]. Starting from four acidic hydroxyazoles with a wide range of pKa values (thiadiazole, pyrazole, triazole and 1,2,5-oxadiazole) [16,18], we first identified compounds with activity in the micromolar range [15,19]. In the following optimization cycle, which involved the 2-hydroxypyrazolo[1,5-a]pyridine scaffold, a lead compound with high on-target activity (sub nanomolar IC50) and low toxicity was identified [20]. In the light of the promising results obtained for the hDHODH, and following the same strategy of scaffold hopping, the authors herein applied a similar strategy to design new inhibitors of PfDHODH. Hydroxyazole-4-carboxamides 2–6 were initially designed in an attempt to mimic the phenol moiety present in the previously described salicylamide 1 (Fig. 2), [21] an inhibitor that showed low micromolar activity and good selectivity towards the P. falciparum enzyme, as compared to hDHODH. Compound 1 itself was the result of an extensive SAR study on salicylamides, conducted through the use of various substituents in the salicylic phenyl ring. The study showed the existence of an inverse correlation between the pKa of the phenolic function and the activity on the enzyme. Compound 1 had the lowest calculated pKa (6.9) and the highest potency (IC50 = 7.0 μM) among tested compounds. Here we will change its benzene scaffold with the aim to improve the acidity of the hydroxyl group and consequently the activity of the resulting compounds. Three acidic hydroxyazoles (hydroxy-1,2,5-oxadiazole, hydroxythiadiazole and hydroxypyrazole), with a range of pKa values [16,22] near or below 6.9, were included in this first series (Fig. 2).