David W Boykin

Georgia State University, Atlanta, Georgia, United States

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Publications (200)619.06 Total impact

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    ABSTRACT: Minor groove binding compounds have been shown to induce changes in global DNA conformation, allosterically inhibiting DNA-protein interactions necessary for transcriptional processes. Many minor groove binders are specific for AT base pairs but have little preference over alternating AT or A-tract sequences. Few compounds, other than polyamides, show selectivity for mixed sequences with AT and GC base pairs. Electrospray ionization mass spectrometry (ESI-MS) can provide insight on the stoichiometry and relative affinities in minor groove recognition of different DNA sequences with a library of minor groove binders. A goal in our current research is to develop new compounds that recognize mixed sequences of DNA. In an effort to optimize screening for compounds that target mixed AT and GC base pair sequences of DNA, ESI-MS was used to study the competitive binding of compounds with a mixed set of DNA sequences. The method identified preferred binding sites, relative affinities, and concentration-dependent binding stoichiometry for the minor groove binding compounds netropsin and DB75 with AT-rich sequences and DB293 with ATGA and AT sites.
    Analytical and Bioanalytical Chemistry 07/2014; · 3.66 Impact Factor
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    ABSTRACT: Fifteen novel bis-arylimidamide derivatives with various 6-membered (7a-c) and 5-membered (7d-o) heterocyclic rings replacing the terminal pyridyl rings of the lead compound DB766{(2,5-bis[2-i-propoxy-4-(2-pyridylimino)aminophenylfuran]}, were prepared and evaluated versus Trypanosoma cruzi, Leishmania amazonensis, Trypanosoma brucei rhodesiense and Plasmodium falciparum. Compound 7a with pyrimidine replacing the pyridine rings showed good activity versus T. cruzi, T. brucei rhodesiense and P. falciparum (IC50 = 200 nM, 32 nM and 8.5 nM, respectively). Three compounds (7g, 7i, 7j) with thiazole replacing the pyridine rings gave low micromolar (0.17-0.3 μM) IC50 values versus L. amazonensis, however only 7g exhibited an acceptable selectivity index (SI = 27). Compounds 7a, 7j and 7m exhibited potent activity against T. brucei rhodesiense (IC50 = 12-60 nM). Ten of the 15 compounds with pyrimidine, pyrrole, thiazole and imidazole terminal units were highly active against P. falciparum (IC50 = 9-87 nM). Both pyrimidine and pyridine terminal groups are advantageous for anti-T. cruzi activity and several different heterocyclic terminal units are effective versus P. falciparum, both findings merit further investigation.
    European journal of medicinal chemistry. 06/2014; 83C:167-173.
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    ABSTRACT: African sleeping sickness is a neglected tropical disease transmitted by tsetse flies. New and better drugs are still needed especially for its second stage, which is fatal if untreated. 28DAP010, a dipyridylbenzene analogue of DB829, is the second simple diamidine found to cure mice with central nervous system infections by a parenteral route of administration. 28DAP010 showed similar efficacy to DB829 in dose response studies in mouse models of first and second stage African sleeping sickness. The in vitro time to kill, determined by microcalorimetry and the parasite clearance time in mice, were shorter for 28DAP010 than for DB829. No cross-resistance was observed between 28DAP010 and pentamidine on the tested T. b. gambiense isolates from melarsoprol-refractory patients. 28DAP010 is the second promising preclinical candidate among the diamidines for the treatment of second stage African sleeping sickness.
    Antimicrobial Agents and Chemotherapy 05/2014; · 4.57 Impact Factor
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    ABSTRACT: Human African trypanosomiasis (HAT), a neglected tropical disease, is fatal without treatment. Pentamidine, a cationic diamidine, has been used to treat first stage (hemolymphatic) HAT since the 1940s, but it is ineffective against second stage (meningoencephalitic or CNS) infection. Novel diamidines (DB75, DB820, and DB829) have shown promising efficacy in both mouse and monkey models of first stage HAT. However, only DB829 cured animals with second stage infection. In this study, we aimed to determine mechanisms underlying the differential efficacy of these diamidines against HAT by conducting a comprehensive pharmacokinetic characterization. This included the determination of metabolic stability in liver microsomes, permeability across MDCK and MDR1-MDCK cell monolayers, interaction with the efflux transporter MDR1 (P-glycoprotein 1 or P-gp), drug binding in plasma and brain, and plasma and brain concentration-time profiles after a single dose in mice. Results showed that DB829, an aza diamidine, had the highest systemic exposure and brain-to-plasma ratio, whereas pentamidine and DB75 were the lowest. None of these diamidines was a P-gp substrate and the binding of each to plasma proteins and brain differed greatly. The brain-to-plasma ratio best predicted the relative efficacy of these diamidines in mice with second stage infection. In conclusion, pharmacokinetics and CNS penetration influenced the in vivo efficacy of cationic diamidines against first and second stage HAT and should be considered when developing CNS-active antitrypanosomal diamidines.
    Antimicrobial Agents and Chemotherapy 05/2014; · 4.57 Impact Factor
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    ABSTRACT: Light-emitting diode (LED) fluorescence microscopy offers potential benefits in the diagnosis of human African trypanosomiasis and in other aspects of diseases management, such as detection of drug-resistant strains. To advance such approaches, reliable and specific fluorescent markers to stain parasites in human fluids are needed. Here we describe a series of novel green fluorescent diamidines and their suitability as probes with which to stain trypanosomes.
    Antimicrobial Agents and Chemotherapy 03/2014; 58(3):1793–1796. · 4.57 Impact Factor
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    ABSTRACT: DB1255 is a symmetrical diamidinophenyl-dithiophene that exhibits cellular activity by binding to DNA and inhibiting binding of ERG, an ETS family transcription factor that is commonly overexpressed or translocated in leukemia and prostate cancer [Nhili, R., Peixoto, P., Depauw, S., Flajollet, S., Dezitter, X., Munde, M. M., Ismail, M. A., Kumar, A., Farahat, A. A., Stephens, C. E., Duterque-Coquillaud, M., Wilson, W. D., Boykin, D. W., and David-Cordonnier, M. H. (2013) Nucleic Acids Res. 41, 125−138]. Because transcription factor inhibition is complex but is an attractive area for anticancer and antiparasitic drug development, we have evaluated the DNA interactions of additional derivatives of DB1255 to gain an improved understanding of the biophysical chemistry of complex function and inhibition. DNase I footprinting, biosensor surface plasmon resonance, and circular dichroism experiments show that DB1255 has an unusual and strong monomer binding mode in minor groove sites that contain a single GC base pair flanked by AT base pairs, for example, 5′-ATGAT-3′. Closely related derivatives, such as compounds with the thiophene replaced with furan or selenophane, bind very weakly to GC-containing sequences and do not have biological activity. DB1255 is selective for the ATGAT site; however, a similar sequence, 5′-ATGAC-3′, binds DB1255 more weakly and does not produce a footprint. Molecular docking studies show that the two thiophene sulfur atoms form strong, bifurcated hydrogen bond-type interactions with the G-N-H sequence that extends into the minor groove while the amidines form hydrogen bonds to the flanking AT base pairs. The central dithiophene unit of DB1255 thus forms an excellent, but unexpected, single-GC base pair recognition module in a monomer minor groove complex.
    Biochemistry 01/2014; 53:1218−1227. · 3.38 Impact Factor
  • Abdelbasset A. Farahat, David W. Boykin
    Tetrahedron Letters 01/2014; 55(19):3049–3051. · 2.40 Impact Factor
  • European Journal of Medicinal Chemistry. 01/2014; 83:167–173.
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    ABSTRACT: LED fluorescence microscopy offers potential benefits to the diagnosis of human African trypanosomiasis, as well as to other aspects of diseases management, such as detection of drug resistant strains. To advance such approaches reliable and specific fluorescent markers to stain parasites in human fluids are needed. Here we report a series of novel green fluorescent diamidines and their suitability as probes to stain trypanosomes.
    Antimicrobial Agents and Chemotherapy 12/2013; · 4.57 Impact Factor
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    ABSTRACT: Heterocyclic diamidines are strong DNA minor-groove binders and have excellent antiparasitic activity. To extend the biological activity of these compounds, a series of arylimidamides (AIAs) analogues, which have better uptake properties in Leishmania and Trypanosoma cruizi than diamidines, was prepared. The binding of the AIAs to DNA was investigated by Tm , fluorescence displacement titration, circular dichroism, DNase I footprinting, biosensor surface plasmon resonance, X-ray crystallography and molecular modeling. These compounds form 1:1 complexes with AT sequences in the DNA minor groove, and the binding strength varies with substituent size, charge and polarity. These substituent-dependent structure and properties provide a SAR that can be used to estimate K values for binding to DNA in this series. The structural results and molecular modeling studies provide an explanation for the differences in binding affinities for AIAs.
    ChemBioChem 12/2013; · 3.74 Impact Factor
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    ABSTRACT: We report here on the discovery and preliminary evaluation of a novel non-macrocyclic low molecular weight quadruplex-stabilizing chemotype. The lead compounds, based on a furan core, show high G-quadruplex stabilisation and selectivity as well as potent in vitro anti-proliferative activity.
    Chemical Communications 12/2013; · 6.38 Impact Factor
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    ABSTRACT: DB844 (CPD-594-12), N-methoxy-6-{5-[4-(N-methoxyamidino)phenyl]-furan-2-yl}-nicotinamidine, is an oral prodrug that has shown promising efficacy in both mouse and monkey models of second stage human African trypanosomiasis. However, gastrointestinal (GI) toxicity was observed with high doses in a vervet monkey safety study. In the current study, we compared the metabolism of DB844 by hepatic and extrahepatic cytochrome P450s to determine whether differences in metabolite formation underlie the observed GI toxicity. DB844 undergoes sequential O-demethylation and N-dehydroxylation in the liver to form the active compound DB820 (CPD-593-12). However, extrahepatic CYP1A1 and CYP1B1 produced two new metabolites, MX and MY. Accurate mass and collision-induced dissociation mass spectrometry analyses of the metabolites supported proposed structures of MX and MY. In addition, MY was confirmed with a synthetic standard and detection of nitric oxide (NO) release when DB844 was incubated with CYP1A1. Taken altogether, we propose that MX is formed by insertion of oxygen into the amidine CN to form an oxaziridine, which is followed by intramolecular rearrangement of the adjacent O-methyl group and subsequent release of NO. The resulting imine ester, MX, is further hydrolyzed to form MY. These findings may contribute to furthering the understanding of toxicities associated with benzamidoxime- and benzmethamidoxime-containing molecules. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
    Journal of Pharmaceutical Sciences 11/2013; · 3.13 Impact Factor
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    ABSTRACT: ETS transcription factors mediate a wide array of cellular functions and are attractive targets for pharmacological control of gene regulation. We report the inhibition of the ETS-family member PU.1 with a panel of novel heterocyclic diamidines. These diamidines are derivatives of furamidine (DB75) in which the central furan has been replaced with selenophene and/or one or both of the bridging phenyl has been replaced with benzimidazole. Like all ETS proteins, PU.1 binds sequence specifically to 10-bp sites by inserting a recognition helix into the major groove of a 5'-GGAA-3' consensus, accompanied by contacts with the flanking minor groove. We showed that diamidines target the minor groove of AT-rich sequences on one or both sides of the consensus and disrupt PU.1 binding. Although all of the diamidines bind to one or both of the expected sequences within the binding site, considerable heterogeneity exists in terms of stoichiometry, site-site interactions and induced DNA conformation. We also showed that these compounds accumulate in live cell nuclei and inhibit PU.1-dependent gene transactivation. This study demonstrates that heterocyclic diamidines are capable of inhibiting PU.1 by targeting the flanking sequences and supports future efforts to develop agents for inhibiting specific members of the ETS family.
    Nucleic Acids Research 10/2013; · 8.81 Impact Factor
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    ABSTRACT: Human African trypanosomiasis (HAT, sleeping sickness), a neglected tropical disease endemic to sub-Saharan Africa, is caused by the parasites Trypanosoma brucei (T. b.) gambiense and T. b. rhodesiense. Current drugs have significant limitations, including toxicity, increasing resistance, and/or a complicated parenteral treatment regimen. DB829 is a novel aza-diamidine that demonstrated excellent efficacy in mice infected with T. b. rhodesiense or T. b. brucei parasites. Current study examined pharmacokinetics, in vitro and in vivo activity against T. b. gambiense, and time of drug action of DB829, in comparison to pentamidine. DB829 showed outstanding in vivo efficacy in mice infected with parasites of T. b. gambiense strains, despite having higher in vitro IC50 values than that against the T. b. rhodesiense STIB900 strain. A single dose of DB829 administered intraperitoneally (5 mg/kg) cured all mice infected with different T. b. gambiense strains. No cross-resistance was observed between DB829 and pentamidine in T. b. gambiense strains isolated from melarsoprol-refractory patients. Compared to pentamidine, DB829 showed a greater systemic exposure when administered intraperitoneally, partially contributing to its improved efficacy. Isothermal microcalorimetry and in vivo time-to-kill studies revealed that DB829 is a slower-acting trypanocidal compound than pentamidine. A single dose of DB829 (20 mg/kg) administered intraperitoneally clears parasites from mouse blood within 2-5 days. In summary, DB829 is a promising preclinical candidate for the treatment of first and second stage HAT caused by both Trypanosoma brucei subspecies.
    Antimicrobial Agents and Chemotherapy 08/2013; · 4.57 Impact Factor
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    ABSTRACT: The effects of salt concentration and temperature on the thermodynamics of DNA minor groove binding have quite different signatures: binding enthalpy is salt concentration independent but temperature dependent. Conversely, binding free energy is salt dependent but essentially temperature independent through enthalpy-entropy compensation.
    Chemical Communications 08/2013; · 6.38 Impact Factor
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    ABSTRACT: Dicationic 2,6-diphenylpyrazines, aza-analogues and prodrugs were synthesized; evaluated for DNA affinity, activity against Trypanosoma brucei rhodesiense (T. b. r.) and Plasmodium falciparum (P. f.) in vitro, efficacy in T. b. r. STIB900 acute and T. b. brucei GVR35 CNS mouse models. Most diamidines gave poly(dA-dT)2 ΔTm values greater than pentamidine, IC50 values: T. b. r. (4.8-37nM) and P. f. (10-52nM). Most diamidines and prodrugs gave cures for STIB900 model (11, 19a and 24b 4/4 cures); 12 3/4 cures for GVR35 model. Metabolic stability half-life values for O-methylamidoxime prodrugs did not correlate with STIB900 results.
    Bioorganic & medicinal chemistry 08/2013; · 2.82 Impact Factor
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    ABSTRACT: Bovine viral diarrhea virus (BVDV) is a widespread bovine pathogen capable of causing disease affecting multiple body systems. Previous studies have shown 2-(2-benzimidazolyl)-5-[4-(2-imidazolino)phenyl]furan dihydrochloride (DB772) effectively prevents BVDV infection in cell culture. The aim of this project was to assess the efficacy of DB772 for the prevention of acute BVDV infection. Four calves seronegative to BVDV were treated with DB772 and another 4 calves were treated with diluent only on the same dosing schedule. Each calf was subsequently challenged intranasally with BVDV. Virus was isolated consistently from untreated calves on days 4 to 8, while treated calves remained negative by virus isolation during this period. Azotemia was exhibited by all treated calves on day 4 resulting in the euthanasia of 1 calf on day 10 and the death of another on day 13. Virus was isolated from the 2 remaining treated calves on day 14 or 21. On day 21, both remaining treated calves and all 4 untreated calves had anti-BVDV antibody titers > 1:2048. This pilot study indicates that DB772 temporarily prevented acute disease due to BVDV, but carries a significant concern of renal toxicity.
    Canadian journal of veterinary research = Revue canadienne de recherche vétérinaire 07/2013; 77(3):170-176. · 1.19 Impact Factor
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    ABSTRACT: Sixty-two cationic benzyl phenyl ether derivatives (36 amidines and 26 prodrugs) were prepared and assayed for activities in vitro and in vivo against Trypanosoma brucei rhodesiense (STIB900), and in vitro against Plasmodium falciparum (K1) and Leishmania donovani axenic amastigotes. 3-Amidinobenzyl 4-amidino-2-iodo-6-methoxyphenyl ether dihydrochloride (55, IC50 = 3.0 nM) and seven other compounds exhibited IC50 values below 10 nM against T. b. rhodesiense in vitro. The 2-bromo-4,4'-diamidino analogue 19 (IC50 = 4.0 nM) and 12 other analogues were more potent than pentamidine (IC50 = 46 nM) against P. falciparum. The 3',4-diamidino-2,6-diiodo analogue 49 (IC50 = 1.4 μM) and two other compounds were more effective than pentamidine (IC50 = 1.8 μM) against L. donovani. A prodrug, 3',4-bis(N″-methoxy)amidino-2-bromo derivative 38, was the most efficacious against trypanosome infected mice, attaining 4/4 cures in four daily 25 mg/kg oral doses, and the 2-chloro-4,4'-diamidine 18 cured 3/4 mice in four daily 5 mg/kg intraperitoneal doses.
    European journal of medicinal chemistry 06/2013; 67C:310-324. · 3.27 Impact Factor
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    ABSTRACT: 4,4″-Diamidino-m-terphenyl (1) and 36 analogues were prepared and assayed in vitro against T rypanosoma brucei rhodesiense , Trypanosoma cruzi , Plasmodium falciparum , and Leishmania amazonensis . Twenty-three compounds were highly active against T. b. rhodesiense or P. falciparum. Most noteworthy were amidines 1, 10, and 11 with IC50 of 4 nM against T. b. rhodesiense, and dimethyltetrahydropyrimidinyl analogues 4 and 9 with IC50 values of ≤ 3 nM against P. falciparum. Bis-pyridylimidamide derivative 31 was 25 times more potent than benznidazole against T. cruzi and slightly more potent than amphotericin B against L. amazonensis. Terphenyldiamidine 1 and dipyridylbenzene analogues 23 and 25 each cured 4/4 mice infected with T. b. rhodesiense STIB900 with four daily 5 mg/kg intraperitoneal doses, as well as with single doses of ≤10 mg/kg. Derivatives 5 and 28 (prodrugs of 1 and 25) each cured 3/4 mice with four daily 25 mg/kg oral doses.
    Journal of Medicinal Chemistry 06/2013; · 5.61 Impact Factor

Publication Stats

2k Citations
619.06 Total Impact Points

Institutions

  • 1987–2014
    • Georgia State University
      • • Department of Chemistry
      • • Center for Biotechnology and Drug Design
      Atlanta, Georgia, United States
  • 2013
    • Universität Basel
      Bâle, Basel-City, Switzerland
    • University of Kansas
      • Department of Pharmaceutical Chemistry
      Lawrence, Kansas, United States
  • 2010–2013
    • Swiss Tropical and Public Health Institute
      Bâle, Basel-City, Switzerland
    • University of Zagreb
      Zagrabia, Grad Zagreb, Croatia
  • 2008–2013
    • Universität Bern
      • Institute of Parasitology
      Bern, BE, Switzerland
  • 2002–2013
    • University of North Carolina at Chapel Hill
      • • Department of Pathology and Laboratory Medicine
      • • Eshelman School of Pharmacy
      • • Division of Molecular Pharmaceutics
      Chapel Hill, NC, United States
    • Walter Reed Army Institute of Research
      Silver Spring, Maryland, United States
  • 1993–2013
    • CSU Mentor
      • Department of Chemistry
      Long Beach, California, United States
  • 2012
    • Washington State University
      Pullman, Washington, United States
    • The Ohio State University
      • Division of Medicinal Chemistry and Pharmacognosy
      Columbus, OH, United States
  • 2006–2012
    • Fundação Oswaldo Cruz
      • Laboratório de Biologia Celular (LBC) (ICC)
      Rio de Janeiro, Rio de Janeiro, Brazil
  • 2003–2012
    • Auburn University
      • • Department of Clinical Sciences
      • • College of Veterinary Medicine
      • • Department of Pathobiology
      Auburn, AL, United States
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • Ohio University
      • Department of Biomedical Sciences
      Athens, OH, United States
  • 2011
    • Mansoura University
      • Department of Chemistry
      Ṭalkha, Muhafazat ad Daqahliyah, Egypt
    • Augusta State University
      • Department of Chemistry and Physics
      Augusta, Georgia, United States
  • 2005
    • University of Glasgow
      Glasgow, Scotland, United Kingdom
    • Ankara University
      • Department of Pharmaceutical Chemistry
      Ankara, Ankara, Turkey
  • 2004
    • University of Louisville
      • Department of Medicine
      Louisville, KY, United States