David Floyd's research while affiliated with McGill University Health Centre and other places

Publications (17)

Article
Full-text available
With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioester...
Article
Full-text available
Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage Plasmodium f...
Data
Table S5. List of clinical M. tuberculosis strains tested, Related to Table 2 and Table S4 This excel file contains all of the drug-resistance conferring mutations found from whole genome sequencing in each of the clinical strains tested in this study.
Article
Full-text available
Widespread resistance to first-line TB drugs is a major problem that will likely only be resolved through the development of new drugs with novel mechanisms of action. We have used structure-guided methods to develop a lead molecule that targets the thioesterase activity of polyketide synthase Pks13, an essential enzyme that forms mycolic acids, re...
Article
Phenotypic whole-cell screening in erythrocytic co-cultures of Plasmodium falciparum identified a series of dihydroisoquinolones that possessed potent anti-malarial activity against multiple resistant strains of P. falciparum in vitro and show no cytotoxicity to mammalian cells. Systematic structure-activity studies revealed relationships between p...
Article
Full-text available
Drug discovery for malaria has been transformed in the last 5 years by the discovery of many new lead compounds identified by phenotypic screening. The process of developing these compounds as drug leads and studying the cellular responses they induce is revealing new targets that regulate key processes in the Plasmodium parasites that cause malari...
Article
The addition of N-methylimidazole (NMI) to the reaction of homophthalic anhydride with imines such as pyridine-3-carboxaldehyde-N-trifluoroethylimine (9) reduces the amount of elimination byproduct and improves the yield of the formal cycloadduct, tetrahydroisoquinolonic carboxylate 10. Carboxanilides of such compounds are of interest as potential...
Article
Full-text available
Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential antimalarials, we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH)...
Article
Malaria is one of the leading causes of severe infectious disease worldwide; yet, our ability to maintain effective therapy to combat the illness is continually challenged by the emergence of drug resistance. We previously reported identification of a new class of triazolopyrimidine-based Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH)...
Article
Full-text available
New antimalarials are urgently needed. We have shown that tetrahydroquinoline (THQ) protein farnesyltransferase (PFT) inhibitors (PFTIs) are effective against the Plasmodium falciparum PFT and are effective at killing P. falciparum in vitro. Previously described THQ PFTIs had limitations of poor oral bioavailability and rapid clearance from the cir...
Article
Substituted tetrahydroquinolines (THQs) have been previously identified as inhibitors of mammalian protein farnesyltransferase (PFT). Previously we showed that blocking PFT in the malaria parasite led to cell death and that THQ-based inhibitors are the most potent among several structural classes of PFT inhibitors (PFTIs). We have prepared 266 THQ-...
Article
New therapeutics to combat malaria are desperately needed. Here we show that the enzyme protein farnesyltransferase (PFT) from the malaria parasite Plasmodium falciparum (P. falciparum) is an ideal drug target. PFT inhibitors (PFTIs) are well tolerated in man, but are highly cytotoxic to P. falciparum. Because of their anticancer properties, PFTIs...

Citations

... Interestingly, the findings of a new lead optimization study of 73 have just been released, where the researchers were seeking to identify a suitable preclinical candidate with a reduced hERG liability. 200 This work was motivated by revised hERG data for 73 (IC 50 6.9 μM) and gave rise to several in vivo active analogues; of these, 74 (Figure 8) was considered to have the best overall profile. Compared to 73, new lead 74 was similarly active against Pks13 (IC 50 0.27 μM) but was 8-fold less potent against Mtb H37Rv (MIC 0.65 vs 0.08 μM for 57) and exhibited minimal hERG inhibition (only 25% at 30 μM). ...
... Lysyl-tRNA synthetase (KRS) was originally identified as the target of cladosporin in P. falciparum. On the basis of structural homology, P. falciparum KRS (PfKRS) inhibitors were tested on C. parvum KRS (CpKRS) and a consortium of investigators led by University of Dundee recently published a comprehensive study of early lead compounds (subsequently referred to in this review as 'leads') targeting both enzymes [13]. A potent chromone compound was reported with excellent drug-like properties ( Table 1). ...
... Wilson et al. screened a NIH library of 1113 compounds in iniBAC reporter assay and identified two lead compounds A and B (Fig. 1) having capability to inhibit mycobacterial growth by targeting Pks13 enzyme [18]. In another study, Aggarwal et al. showed that TAM16, a benzofuran scaffold inhibits thioesterase activity associated with Pks13 [23]. A small molecule C was identified using NMR based fragment screening of antigen 85C [20]. ...
... Scheme 1. Castagnoli and Castagnoli-Cushman reactions. Moreover, these cycloaddition reactions have seen wide applications in the synthesis of medicinal lead compounds piperidines and piperidinones derivatives [4,5], sting antagonist [6], and antimalarial [7] or anticancer agents [8][9][10]. In addition, lactams obtained by these reactions, and their reduced nitrogen heterocycle analogs are found to be key intermediates in the synthesis of biologically significant natural products such as 13-methyltetrahydroprotoberbines (i.e., (+)-thalictricavine, (+)-canadine, (+) and (−)cavidine [11][12][13], phenanthridine alkaloids and (−) and (+)-corynoline [14] possessing antitumor activity [15] (Figure 1). ...
... We recently participated in the development of SJ733 (Figure 1), an ATP4 inhibitor now in phase 2 clinical trials [4][5][6], and also explored improvements in its synthesis [7][8][9][10]. The tetrahydroisoquinolin-1-one (THIQ) 4-carboxanilide core requires an amidation reaction as a key step. ...
... 1-3 SJ733 is a newly developed orally available inhibitor of Plasmodium falciparum ATP4 (PfATP4), a critical sodium-proton antiporter in the parasite and the second in class, after cipargamin, to enter clinical development. [4][5][6][7][8] Its major metabolite SJ506 has no known antimalarial activity. ...
... We recently participated in the development of SJ733 (Figure 1), an ATP4 inhibitor now in phase 2 clinical trials [4][5][6], and also explored improvements in its synthesis [7][8][9][10]. The tetrahydroisoquinolin-1-one (THIQ) 4-carboxanilide core requires an amidation reaction as a key step. ...
... The other strategy utilizing high-throughput screening is mainly based on target-based approaches, as seen in the small-molecule drug discovery. Using these approaches, the dihydroorotate dehydrogenase (DHODH) inhibitor DSM265, 7 the serine hydroxymethyltransferase (SHMT) inhibitor (+)-86, 8 and the proteasome inhibitor MPI-1 pinane ester 9 were successfully discovered ( Fig. 1(B)). For the purpose of efficiently identifying lead compounds with novel mechanisms, the search for new antimalarials has recently shifted from target-based approaches toward cell-based phenotypic Scheme 1. Reagents and conditions: (a) R 1 COCH 2 CO 2 R', H 2 SO 4 or p-TsOH⋅H 2 O, rt, 15-94%; (b) 1) R 2 CH(OH)CO 2 Me, DIAD, TPP, THF, rt, 2) aq. ...
... A considerable effort has been made to develop triazolopyrimidines with antimalarial properties. [22][23][24][25] Moreover, triazolopyrimidine derivatives are ligands that display a great versatility in their interaction with metal ions, not only because they can bind the metal ion at different positions but also because their presence influences the behavior of other auxiliary ligands. This can occur either by electronic or steric effects, giving rise in some cases to compounds with unusual metal-metal interactions. ...
... [31][32][33][34][35] Later on, these farnesyltransferase inhibitors were found to be highly efficacious in the treatment of pathogenic protozoa such as Trypanosoma brucei and Plasmodium falciparum and the protein farnesyltransferase has emerged as a significant target for the development of novel generation of antimalarial agents. [36][37][38][39][40] In the absence of a crystal structure of P. falciparum farnesyltransferase (PfFT), only a homology model can be used through comparison with its mammalian orthologs. Indeed, numerous mammalian FTinhibitor co-crytsal structures are reported in the literature and almost all inhibitors bind to the Ca1a2X portion of the active site that is normally occupied by the protein substrate. ...