br Result and discussion br Conclusions In this paper

Result and discussion
Conclusions In this paper we introduced a new generation of hDHODH inhibitors designed by scaffold hopping replacement of the acidic moiety of brequinar with different hydroxylated azoles. All the designed compounds can potently inhibit hDHODH in vitro, reaching an IC50 value of 16 nM in the best example, the thiadiazole 4. Moreover, when tested for antiproliferative activity, compounds 3–9 (but not 6a and 6b) were found to be effective in the same range of concentration as brequinar. In addition, compounds 4, 5 and 6 have lower cellular cytotoxicity than the leads, showing cytotoxic effects at 70-fold higher concentrations than those required to inhibit cell proliferation. These three promising hDHODH inhibitors, for which evidence suggests that antiproliferative activity depends on blocking the de novo PF-03814735 mg biosynthesis, were tested for their immunosuppression activity showing promising effects on PBMC, similarly to brequinar. Compounds 4, 5 and 6 therefore represent original chemical scaffolds explored in the field of hDHODH inhibition and might lead to the discovery of new immunosuppressant and antiproliferative agents targeting hDHODH. The crystal structures of the most interesting hDHODH inhibitors from series 4, 5 and 6 will facilitate subsequent optimization both in terms of drug-like properties and pharmacokinetic characteristics. In addition, optimized analogues could undergo in vivo tests (e.g. collagen-induced arthritis, CIA) to evaluate their anti-arthritic activity. These studies are under development and will be the subjects of forthcoming publications.
Experimental section
Notes
PDB ID codes The atomic coordinates and structure factors of hDHODH in complex with compounds 4 (PDB id: 5MVC), 5 (PDB id: 5MVD) and 6 (PDB id: 5MUT) have been deposited in the RCSB Protein Data Bank.
Acknowledgements This research was financially supported by the University of Turin (Ricerca Locale grant 2015 (LOLMAUTO00) and 2014 (LOLM_RIC_LOC_14_01)). CHA and RCB received financial support from (LOLM_RIC_LOC_14_01) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil, 481392/2013-0) and Fundação de Amparo à Pesquisa do Estado de Goiás (FAPEG, Brazil, 201210267001112 and 201310267001105). RF and MA acknowledge support from ESS & MAXIV: Cross Border network and postgraduate education programme MAX4ESSFUN. CHA is CNPq productivity fellow (310025/2015-0) and PG is long term EMBO fellow (ALTF 1163-2014). A-CM is thankful for a grant from the Equal Opportunities Commission of the Faculty of Chemistry of Bielefeld University. RCB and CHA would like to thank ChemAxon for providing the academic license of their software, as well as Brazilian funding agencies CNPq, CAPES and FAPEG.
Malaria is caused by five species of apicomplexan parasites of the genus that affect humans. The most deadly form is caused by . and predominates in Africa, whereas . is less dangerous but more widespread. In 2013, 198 million cases were estimated to have occurred globally, and the disease killed 367,000 to 755,000 people , with children under 5 years of age and pregnant women being most severely affected. Resistance to artemisinins—the key compounds in artemisinin-based combination therapies—has been detected in five countries of Southeast Asia: Cambodia, the Lao People\'s Democratic Republic, Myanmar, Thailand, and Viet Nam. Although such resistance has not yet led to operational failure of malaria control programs, urgent and intensified efforts are required to prevent a future public health disaster and new and differentiated treatments are needed.