2-Pyridylquinolone antimalarials with improved antimalarial activity and physicochemical properties

Abstract

A series of 2-pyridylquinolones has been prepared in 5-7 steps and through lead optimisation, antimalarial activity as low as 12 nM against Plasmodium falciparum (Pf) has been achieved. Compared with previous analogues in this series, selected molecules have improved solubility, a reduced potential for off-target toxicity and improved metabolic stability profiles. Docking studies performed with a homology model of the Pfbc1 complex target demonstrate a key role for the Tyr16 residues in the recognition of highly active quinolone based inhibitors. Page 1 of 13 MedChemComm MedChemComm Accepted Manuscript IntroductionMalaria is caused by parasites of the genus Plasmodium which are widespread in tropical and subtropical regions of the world and is responsible for one million deaths every year 1 . Plasmodium falciparum is the most deadly form of the parasite transmitted to the human host by Anopheles mosquitoes 2 and has developed resistance to many of the established classes of drugs 3 . Due to drug resistance, the discovery of novel drug candidates remains a top priority. The development of compounds focused on hitting new targets is seen as a viable way forward and is an established approach to avoid cross resistance with available antimalarials 4 . There are a large number of recent studies based on the development of antimalarials with quinolone-related structures [5][6][7] . One of these programmes resulted in the discovery of ELQ-300, a selective cytochrome bc 1 inhibitor now in pre-clinical development [8][9][10] . Our recent work has shown that inhibition of two mitochondrial enzymes in the electron transport chain -the cytochrome bc 1 complex and the recently identified PfNDH2 (Type II NADH:ubiquinone oxidoreductase) 11, 12 -results in the collapse of the mitochondrial membrane potential and to the inhibition of de novo pyrimidine biosynthesis and ultimately parasite death 13. Since effective dual inhibition of these proteins can be observed with the 2-aryl and 2-pyridylquinolone pharmacophore 14a a number of inhibitors based on this structure have been identified. Two such lead compounds are CK-2-68 and SL-2-25 (1) -both of which confer potent nanomolar activity against asexual and liver stages of P. falciparum 15,16 ( Figure 1). Here, we describe further modifications of the quinolone A-ring and 2-pyridyl side chain with the aim of reducing lipophilicity in an attempt to provide compounds with improved activity/solubility profiles.In order to increase polarity of our quinolone hit series we incorporated a hydroxyl group into the A-ring at one of the 6, 7 or 8-positions. The inclusion of the hydroxyl group in the quinolone A-ring offered the option of exploring pro-drugs for the series by derivatisation to provide either phosphate or carbamate pro-drugs. Since the corresponding methoxy analogues were prepared en route to 23 -25, these compounds were also screened against Plasmodium falciparum. Results and discussionThe synthesis of the methoxy and hydroxy series was accomplished in 5-7 steps from commercia...

X-ray and cryo-EM structures of inhibitor-bound cytochromebc1complexes for structure-based drug discovery

“…We used cryo-EM to study the structure of bc 1 in complex with inhibitors from two different families with a pyridone (GSK932121; Bueno et al, 2012) or quinolone (SCR0911; Charoensutthivarakul et al, 2015) core, along with the apo complex. The apo data set was resolved to a global resolution of 4.4 Å and the two inhibitor-bound complexes were both determined to 4.1 Å resolution as calculated by Fourier shell correlation (FSC = 0.143; Scheres & Chen, 2012; Supplementary Fig.…”

“…2-Pyridylquinolones have been developed for antimalarial activity, with a mechanism of dual inhibition of NADH:ubiquinone oxidoreductase (Pf NDH2) and bc 1 (Pidathala et al, 2012;Biagini et al, 2012). One quinolone, SCR0911, has been reported to have improved solubility and metabolic stability, with nanomolar activity against P. falciparum ( Charoensutthivarakul et al, 2015).…”

New Opportunities in the Structure-based Design of Anti-Protozoan Agents

“…Many recent compound series based on 4-(1H)-quinolone/4-pyridone scaffolds are also proposed to bind to the Qi site [44]. This motif appears to be a privileaged scaffold for the inhibition of cytochrome bc1 in both Plasmodium and Toxoplasma [44][45][46][47][48]. There are a number of advantages to targeting the Qi site: (i) targeting a novel site within a validated target increases confidence that inhibition of this target will have the desired phenotypic response; (ii) there are no existing resistance mechanisms.…”

“…In these compounds, it was observed there was a delicate balance between compounds inhibiting at the Qo site and the Qi site, and that this could be effected by subtle changes in the compounds structures. However, the rationalisation discussed was based on a 'flipped' conformation of the inhibitor within the binding site which was based on a homology model of the Plasmodium cytochrome bc1 [44].…”

“…This discovery confirms that the Qi site is druggable and facilitates new structure-based design opportunities at this binding site. Many recent compound series based on 4-(1H)-quinolone/4-pyridone scaffolds are also proposed to bind to the Qi site [44]. This motif appears to be a privileaged scaffold for the inhibition of cytochrome bc1 in both Plasmodium and Toxoplasma [44][45][46][47][48].…”