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  • br Inhibition of DHODH The final products a n were


    Inhibition of DHODH The final products 7a–n were assessed for their DHODH inhibitory activity on rat liver mitochondrial/microsomal membranes. A procedure adapted from the literature was employed (see Experimental), in which oxidation of DHO to ORO is monitored by following the concomitant reduction of the chromophore 2,6-dichlorophenolindophenol (DCIP) [24]; A771726 and BQN were taken as references. The reduction of DCIP was detected by the decrease in absorbance at 650 nm. The initial rate of the enzymatic reaction in the presence (v) and in the absence (V) of inhibitor was measured, and the IC50 value was calculated from Eq. (1):where [I] is the concentration of the inhibitor. The results are collected in Table 1.
    Results and discussion
    Conclusions This study shows that it is possible to obtain a new class of DHODH inhibitors by joining the 4-hydroxy-1,2,5-oxadiazol-3-yl scaffold to substituted biphenyl moieties through an amide bridge. SAR analyses show that the most active compounds bear two or four fluorine atoms at the phenyl ring adjacent to the amide group. The introduction of the trifluoromethoxy group at the 3′-position of the distal phenyl of 7m affords 7n, which is an inhibitor as potent as BQN. A molecular modeling study rationalizes the beneficial role of the fluorine substituents, showing that the latter enhance interactions with the 4 methylumbelliferone ubiquinone channel of the enzyme, and stabilize the putative bioactive conformation. While the majority of docking results indicate that these inhibitors adopt a brequinar-like binding mode, additional evidences are necessary to say a conclusive word on this point.
    Experimental part
    Acknowledgments Chemical Computing Group is acknowledged for financial support to computational work.
    Introduction Liquid phase combinatorial synthetic technique is well known for the synthesis of library of compounds. A corresponding method is to practise solution-phase chemistry using support-bound chemicals or support-bound scavengers to enable the elimination of impurities or extra reagents from the solution comprising the anticipated library members [1]. By means of polymer-bound components; the combinatorial chemistry is developed as a well-organised device to construct small molecule libraries for fast-tracking the drug discovery procedure [2]. The poly (ethylene glycol) support plays as a portion of ester linkage that is made free at the final step [3]. Soluble matrixes such as poly (ethylene glycol)-PEG [4], fluorous supports, and linear poly (styrene) have just established collective consideration for their effectiveness in producing varied molecules. To encounter all necessities of a stepwise synthesis deprived of in-between purification, a soluble matrix should be steady through a wide variety of reaction environments. The benzimidazole ring organisation is basically associated with the broadly used benzodiazepine nucleus and has not been extensively used in medicinal chemistry. In addition, benzimidazole centred compounds have revealed wide-ranging biological actions, comprising of antiulcer, antihistaminic, antiparasitic and antiviral properties. An overall technique for the fast manifold synthesis of benzimidazoles would be of countless importance and virtues exploration for drug discovery [5], [6]. Liquid phase combinatorial synthesis approach is widely applied for the synthesis of compounds which can be screened for certain biological activity and a library of compounds can be prepared. Dihydroorotate dehydrogenase (DHODH) is an enzyme essential to the fourth and rate-limiting step in de novo pyrimidine biosynthesis and it catalyses the conversion of dihydroorotate (DHO) to orotate (ORO) with the reduction of ubiquinone. The significance of pyrimidine bases for metabolism, cell and proliferation determines human DHODH as an attractive chemotherapeutic target for the development of new drug candidates in different biological and clinical applications for cancer, arthritis and malaria [7], [8]. Leflunomide and brequinar are the most successful examples of low-molecular weight inhibitors of hDHODH. Leflunomide is the first hDHODH inhibitor that was approved for use in human medicine in the treatment of rheumatoid arthritis and turns out to be a pro-drug to the active metabolite A771726, while brequinar is an antitumor and immunosuppressive agent which shows immunosuppressive activity. Unfortunately, severe side effects like leukocytopenia, mucositis and abnormalities in liver enzymes were observed during clinical use of brequinar and lefluonomide. Consequently, more efficient hDHODH inhibitors are needed as potential prototypes for synthesis of new hDHODH inhibitors [7], [8], [9], [10].