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1.  Bioisosteric transformations and permutations in the triazolopyrimidine scaffold to identify the minimum pharmacophore required for inhibitory activity against Plasmodium falciparum dihydroorotate dehydrogenase 
Journal of medicinal chemistry  2012;55(17):7425-7436.
Plasmodium falciparum causes approximately 1 million deaths annually. However increasing resistance imposes a continuous threat to existing drug therapies. We previously reported a number of potent and selective triazolopyrimidine-based inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase that inhibit parasite in vitro growth with similar activity. Lead optimization of this series led to the recent identification of a preclinical candidate, showing good activity against P. falciparum in mice. As part of a backup program around this scaffold, we explored heteroatom rearrangement and substitution in the triazolopyrimidine ring and have identified several other ring configurations that are active as PfDHODH inhibitors. The imidazo[1,2-α]pyrimidines were shown to bind somewhat more potently than the triazolopyrimidines depending on the nature of the amino aniline substitution. DSM151, the best candidate in this series, binds with 4-fold better affinity (PfDHODH IC50 = 0.077 μM) than the equivalent triazolopyrimidine and suppresses parasites in vivo in the P. berghei model.
doi:10.1021/jm300351w
PMCID: PMC3446820  PMID: 22877245
2.  Urea-based inhibitors of Trypanosoma brucei methionyl-tRNA synthetase: selectivity and in vivo characterization 
Journal of medicinal chemistry  2012;55(14):6342-6351.
Urea-based methionyl-tRNA synthetase inhibitors were designed, synthesized and evaluated for their potential towards treating human African trypanosomiasis (HAT). With the aid of a homology model and a structure-activity-relationship approach, low nM inhibitors were discovered that show high selectivity towards the parasite enzyme over the closest human homolog. These compounds inhibit parasite growth with EC50 values as low as 0.15 μM while having low toxicity to mammalian cells. Two compounds (2 and 26) showed excellent membrane permeation in the MDR1-MDCKII model, and encouraging oral pharmacokinetic properties in mice. Compound 2 was confirmed to enter the CNS in mice. Compound 26 had modest suppressive activity against T. brucei rhodesiense in the mouse model, suggesting that more potent analogs or compounds with higher exposures need to be developed. The urea-based inhibitors are thus a promising starting point for further optimization towards the discovery of orally available and CNS active drugs to treat HAT.
doi:10.1021/jm300303e
PMCID: PMC3480199  PMID: 22720744
3.  Lead-optimization of aryl and aralkyl amine based triazolopyrimidine inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with antimalarial activity in mice 
Journal of medicinal chemistry  2011;54(11):3935-3949.
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 P. falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors with antimalarial activity, leading to the discovery of a new lead series and novel target for drug development. Active compounds from the series contained a triazolopyrimidine ring attached to an aromatic group through a bridging nitrogen atom. Herein we describe systematic efforts to optimize the aromatic functionality with the goal of improving potency and in vivo properties of compounds from the series. These studies led to the identification of two new substituted aniline moieties (4-SF5-Ph and 3,5-Di-F-4-CF3-Ph) which, when coupled to the triazolopyrimidine ring showed good plasma exposure and better efficacy in the P. berghei mouse model of the disease, than previously reported compounds from the series.
doi:10.1021/jm200265b
PMCID: PMC3124361  PMID: 21517059
4.  The Protein Farnesyltransferase Inhibitor Tipifarnib as a new Lead for the Development of Drugs against Chagas Disease 
Journal of Medicinal Chemistry  2005;48(17):5415-5418.
Tipifarnib (R115777), an inhibitor of human protein farnesyltransferase (PFT), is shown to be a highly potent inhibitor of Trypanosoma cruzi growth (ED50 = 4 nM). Surprisingly, this is due to the inhibition of cytochrome P450 sterol 14-demethylase (CYP51, EC 1.14.13.70). Homology models of the T. cruzi CYP51 were used for the prediction of the binding modes of the substrate lanosterol and of Tipifarnib, providing a basis for the design of derivatives with selectivity for TcCYP51 over human PFT.
doi:10.1021/jm050441z
PMCID: PMC3265986  PMID: 16107140
5.  Second Generation Analogs of the Cancer Drug Clinical Candidate Tipifarnib for Anti-Chagas Disease Drug Discovery 
Journal of medicinal chemistry  2010;53(10):3887-3898.
We previously reported that the cancer drug clinical candidate tipifarnib kills the causative agent of Chagas disease, Trypanosoma cruzi, by blocking ergosterol biosynthesis at the level of inhibition of lanosterol 14α-demethylase. Tipifarnib is an inhibitor of human protein farnesyltransferase. We synthesized tipifarnib analogs that no longer bind to protein farnesyltransferase and display increased potency for killing parasites. This was achieved in a structure-guided fashion by changing the substituents attached to the phenyl group at the 4-position of the quinoline ring of tipifarnib and by replacing the amino group by OMe. Several compounds that kill Trypanosoma cruzi at sub-nanomolar concentrations and are devoid of protein farnesyltransferase inhibition were discovered. The compounds are shown to be advantageous over other lanosterol 14α-demethylase inhibitors in that they show only modest potency for inhibition of human cytochrome P450 (3A4). Since tipifarnib displays high oral bioavailability and acceptable pharmacokinetic properties, the newly discovered tipifarnib analogs are ideal leads for the development of drugs to treat Chagas disease.
doi:10.1021/jm9013136
PMCID: PMC2877169  PMID: 20429511
cytochrome P450; Chagas disease; drug discovery; sterol biosynthesis; structure-based drug design
6.  Potent, Plasmodium-Selective Farnesyltransferase Inhibitors That Arrest the Growth of Malaria Parasites: Structure—Activity Relationships of Ethylenediamine-Analogue Scaffolds and Homology Model Validation 
Journal of medicinal chemistry  2008;51(17):5176-5197.
New chemotherapeutics are urgently needed to combat malaria. We previously reported on a novel series of antimalarial, ethylenediamine-based inhibitors of protein farnesyltransferase (PFT). In the current study, we designed and synthesized a series of second generation inhibitors, wherein the core ethylenediamine scaffold was varied in order to examine both the homology model of Plasmodium falciparum PFT (PfPFT) and our predicted inhibitor binding mode. We identified several PfPFT inhibitors (PfPFTIs) that are selective for PfPFT versus the mammalian isoform of the enzyme (up to 136-fold selectivity), that inhibit the malarial enzyme with IC50 values down to 1 nM, and that block the growth of P. falciparum in infected whole cells (erythrocytes) with ED50 values down to 55 nM. The structure–activity data for these second generation, ethylenediamine-inspired PFT inhibitors were rationalized by consideration of the X-ray crystal structure of mammalian PFT and the homology model of the malarial enzyme.
doi:10.1021/jm800113p
PMCID: PMC3049929  PMID: 18686940
7.  Adenosine Analogues as Selective Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase of Trypanosomatidae via Structure-Based Drug Design 
Journal of medicinal chemistry  2001;44(13):2080-2093.
In our continuation of the structure-based design of anti-trypanosomatid drugs, parasite-selective adenosine analogues were identified as low micromolar inhibitors of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Crystal structures of Trypanosoma brucei, Trypanosoma cruzi, Leishmania mexicana, and human GAPDH’s provided details of how the adenosyl moiety of NAD+ interacts with the proteins, and this facilitated the understanding of the relative affinities of a series of adenosine analogues for the various GAPDH’s. From exploration of modifications of the naphthalenemethyl and benzamide substituents of a lead compound, N6-(1-naphthalenemethyl)-2′-deoxy-2′-(3-methoxybenzamido)adenosine (6e), N6-(substituted-naphthalenemethyl)-2′-deoxy-2′-(substituted-benzamido)adenosine analogues were investigated. N6-(1-Naphthalenemethyl)-2′-deoxy-2′-(3,5-dimethoxybenzamido)adenosine (6m), N6-[1-(3-hydroxy-naphthalene)methyl]-2′-deoxy-2′-(3,5-dimethoxybenzamido)adenosine (7m), N6-[1-(3-methoxy-naphthalene)methyl]-2′-deoxy-2′-(3,5-dimethoxybenzamido)adenosine (9m), N6-(2-naphthalene-methyl)-2′-deoxy-2′-(3-methoxybenzamido)adenosine (11e), and N6-(2-naphthalenemethyl)-2′-deoxy-2′-(3,5-dimethoxybenzamido)adenosine (11m) demonstrated a 2- to 3-fold improvement over 6e and a 7100- to 25000-fold improvement over the adenosine template. IC50’s of these compounds were in the range 2–12 μM for T. brucei, T. cruzi, and L. mexicana GAPDH’s, and these compounds did not inhibit mammalian GAPDH when tested at their solubility limit. To explore more thoroughly the structure–activity relationships of this class of compounds, a library of 240 N6-(substituted)-2′-deoxy-2′-(amido)adenosine analogues was generated using parallel solution-phase synthesis with N6 and C2′ substituents chosen on the basis of computational docking scores. This resulted in the identification of 40 additional compounds that inhibit parasite GAPDH’s in the low micromolar range. We also explored adenosine analogues containing 5′-amido substituents and found that 2′,5′-dideoxy-2′-(3,5-dimethoxy-benzamido)-5′-(diphenylacetamido)adenosine (49) displays an IC50 of 60–100 μM against the three parasite GAPDH’s.
PMCID: PMC2957370  PMID: 11405646
8.  Second Generation Tetrahydroquinoline-Based Protein Farnesyltransferase Inhibitors as Antimalarials 
Journal of medicinal chemistry  2007;50(19):4585-4605.
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-based PFTIs and discovered several compounds that inhibit the malarial enzyme in the sub- to low-nanomolar range and that block the growth of the parasite (P. falciparum) in the low-nanomolar range. This body of structure–activity data can be rationalized in most cases by consideration of the X-ray structure of one of the THQs bound to mammalian PFT together with a homology structural model of the malarial enzyme. The results of this study provide the basis for selection of antimalarial PFTIs for further evaluation in preclinical drug discovery assays.
doi:10.1021/jm0703340
PMCID: PMC2894570  PMID: 17722901
9.  Structurally Simple Inhibitors of Lanosterol 14α-Demethylase Are Efficacious In a Rodent Model of Acute Chagas Disease 
Journal of medicinal chemistry  2009;52(12):3703-3715.
We report structure-activity studies of a large number of dialkyl imidazoles as inhibitors of Trypanosoma cruzi lanosterol-14α-demethylase (L14DM). The compounds have a simple structure compared to posaconazole, another L14DM inhibitor that is an anti-Chagas drug candidate. Several compounds display potency for killing T. cruzi amastigotes in vitro with values of EC50 in the 0.4–10 nM range. Two compounds were selected for efficacy studies in a mouse model of acute Chagas disease. At oral doses of 20–50 mg/kg given after establishment of parasite infection, the compounds reduced parasitemia in the blood to undetectable levels, and analysis of remaining parasites by PCR revealed a lack of parasites in the majority of animals. These dialkyl imidazoles are substantially less expensive to produce than posaconazole and are appropriate for further development toward an anti-Chagas disease clinical candidate.
doi:10.1021/jm900030h
PMCID: PMC2771698  PMID: 19463001
10.  Structurally Simple, Potent, Plasmodium Selective Farnesyltransferase Inhibitors That Arrest the Growth of Malaria Parasites 
Journal of medicinal chemistry  2006;49(19):5710-5727.
Third world nations require immediate access to inexpensive therapeutics to counter the high mortality inflicted by malaria. Here, we report a new class of antimalarial protein farnesyltransferase (PFT) inhibitors, designed with specific emphasis on simple molecular architecture, to facilitate easy access to therapies based on this recently validated antimalarial target. This novel series of compounds represents the first Plasmodium falciparum selective PFT inhibitors reported (up to 145-fold selectivity), with lead inhibitors displaying excellent in vitro activity (IC50 < 1 nM) and toxicity to cultured parasites at low concentrations (ED50 < 100 nM). Initial studies of absorption, metabolism, and oral bioavailability are reported.
doi:10.1021/jm060081v
PMCID: PMC2728208  PMID: 16970397
11.  Rational Modification of a Candidate Cancer Drug for Use Against Chagas Disease 
Journal of medicinal chemistry  2009;52(6):1639-1647.
Chagas disease is one of the major neglected diseases of the world. Existing drug therapies are limited, ineffective and highly toxic. We describe a novel strategy of drug discovery of adapting an existing clinical compound with excellent pharmaceutical properties to target a pathogenic organism. The protein farnesyltransferase (PFT) inhibitor tipifarnib, now in phase III anti-cancer clinical trials, was previously found to kill Trypanosoma cruzi by blocking sterol 14α-demethylase (14DM). We rationally developed tipifarnib analogs that display reduced affinity for human PFT to reduce toxicity, while increasing affinity for parasite 14DM. The lead compound has picomolar activity against cultured T. cruzi and is efficacious in a mouse model of acute Chagas disease.
doi:10.1021/jm801313t
PMCID: PMC2715367  PMID: 19239254

Results 1-11 (11)