Manipulating Solid Forms of Contact Insecticides for Infectious Disease Prevention

Article abstract of DOI:10.1021/jacs.9b08125

Malaria control is under threat by the development of vector resistance to pyrethroids in long-lasting insecticidal nets, which has prompted calls for a return to the notorious crystalline contact insecticide DDT. A faster acting difluoro congener, DFDT, was developed in Germany during World War II, but in 1945 Allied inspectors dismissed its superior performance and reduced toxicity to mammals. It vanished from public health considerations. Herein, we report the discovery of amorphous and crystalline forms of DFDT and a mono-fluorinated chiral congener, MFDT. These solid forms were evaluated against Drosophila as well as Anopheles and Aedes mosquitoes, the former identified as disease vectors for malaria and the latter for Zika, yellow fever, dengue, and chikungunya. Contact insecticides are transmitted to the insect when its feet contact the solid surface of the insecticide, resulting in absorption of the active agent. Crystalline DFDT and MFDT were much faster killers than DDT, and their amorphous forms were even faster. The speed of action (a.k.a. knockdown time), which is critical to mitigating vector resistance, depends inversely on the thermodynamic stability of the solid form. Furthermore, one enantiomer of the chiral MFDT exhibits faster knockdown speeds than the other, demonstrating chiral discrimination during the uptake of the insecticide or when binding at the sodium channel, the presumed destination of the neurotoxin. These observations demonstrate an unambiguous link between thermodynamic stability and knockdown time for important disease vectors, suggesting that manipulation of the solid-state chemistry of contact insecticides, demonstrated here for DFDT and MFDT, is a viable strategy for mitigating insect-borne diseases, with an accompanying benefit of reducing environmental impact.

Full text of DOI:10.1021/jacs.9b08125

Article
pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Manipulating Solid Forms of Contact Insecticides for Infectious
Disease Prevention
Xiaolong Zhu,† Chunhua T. Hu,† Jingxiang Yang,† Leo A. Joyce,‡ Mengdi Qiu,†
Michael D. Ward,*,† and Bart Kahr*,†
†Department of Chemistry and Molecular Design Institute, New York University, 100 Washington Square East, New York, New
York 10003 United States
‡Department of Process Research & Development, Merck & Co, Inc., Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: Malaria control is under threat by the development of vector resistance to
pyrethroids in long-lasting insecticidal nets, which has prompted calls for a return to the
notorious crystalline contact insecticide DDT. A faster acting difluoro congener, DFDT, was
developed in Germany during World War II, but in 1945 Allied inspectors dismissed its superior
performance and reduced toxicity to mammals. It vanished from public health considerations.
Herein, we report the discovery of amorphous and crystalline forms of DFDT and a mono-
fluorinated chiral congener, MFDT. These solid forms were evaluated against Drosophila as well
as Anopheles and Aedes mosquitoes, the former identified as disease vectors for malaria and the
latter for Zika, yellow fever, dengue, and chikungunya. Contact insecticides are transmitted to
the insect when its feet contact the solid surface of the insecticide, resulting in absorption of the
active agent. Crystalline DFDT and MFDT were much faster killers than DDT, and their
amorphous forms were even faster. The speed of action (a.k.a. knockdown time), which is
critical to mitigating vector resistance, depends inversely on the thermodynamic stability of the
solid form. Furthermore, one enantiomer of the chiral MFDT exhibits faster knockdown speeds than the other, demonstrating
chiral discrimination during the uptake of the insecticide or when binding at the sodium channel, the presumed destination of
the neurotoxin. These observations demonstrate an unambiguous link between thermodynamic stability and knockdown time
for important disease vectors, suggesting that manipulation of the solid-state chemistry of contact insecticides, demonstrated
here for DFDT and MFDT, is a viable strategy for mitigating insect-borne diseases, with an accompanying benefit of reducing
environmental impact.
address acknowledging his discovery of DDT,8 argued that
faster-acting DFDT should be the insecticide of the future.
INTRODUCTION
■
Agents for combatting infectious diseases may be in full view,
Forward-thinking scientists recognized that speed of insect
but not always seen. Artemisinin-based malaria therapies were
knockdown is essential for combatting resistance to exogenous
not so much discovered as rediscovered, inspired by ancient
chemical agents.9,10 Inexpensive DDT, however, was achieving
everything asked of it and was marshalled for the eradication of
malaria by the World Health Organization (WHO) in 1955.11
DDT nevertheless faltered in the face of insect resistance12 and
experienced a backlash in the wake of serious environmental
concerns, foretold by Rachel Carson in Silent Spring.13 From
2006 to 2015, indoor residual spraying (IRS) of DDT was
recommended by the WHO as a primary tool for controlling
malaria.14,15 In a 2019 report, however, the WHO retreated
from their earlier position, recommending DDT for IRS only
when other compounds were ineffective.16 Nonetheless, an
accurate reading of history suggests that DDT would have
remained effective for infectious disease mitigation if it had not
been used in such a cavalier manner for agricultural
applications.
pharmacopeias.1 Malaria and other vector-borne diseases also
can be mitigated by insecticides. During the 20th century DDT
(1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane; Figure 1a),
which was patented by the Swiss company J. R. Geigy S. A.
in 1939, was the most commonly used contact insecticide.2,3
A
contact insecticide overlooked by the public health community
is DFDT (1,1,1-trichloro-2,2-bis(4-fluorophenyl)ethane; Fig-
ure 1a), known as Gix among other names.3 DFDT was
developed by the German company, Hochst A. G., to
circumvent paying of royalties for the use of DDT. Hochst
manufactured 40 tons/month of DFDT during World War II
for the German army in North Africa and on the eastern front.4
Meanwhile, American authorities considered DDT “magic”.5
Combined military and post-war civilian spraying campaigns
covered the planet with two million tons of DDT.6
̈
̈
DFDT manufacture ended abruptly in the post-war chaos
and was never revived. Victorious Allied military officials
dismissed German claims of DFDT’s fast action against pests
Received: July 29, 2019
and lower toxicity to mammals.7 Mu
̈
ller, in his 1948 Nobel
© XXXX American Chemical Society
A
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Figure 1. Solid-state forms of DFDT and MFDT. (a) Molecular structures. (b) DFDT-I (space group, P21/c) is isostructural with (RS)-MFDT-II
(Supporting Information, Figure S7). (c) DFDT-II (P21/c). (d) (RS)-MFDT-I (P1). (e) (R)-, and (f) (S)-MFDT (P21). (g) (RS)-MFDT-III
(Pbca). (h) Broad powder X-ray diffraction (PXRD) halos observed for amorphous forms. Atom colors: hydrogen, white; carbon, gray; fluorine,
magenta; chlorine, green.
Numerous strategies have been pursued for the treatment of
malaria infection, largely through the design of therapeutics
aimed at the cellular level of the parasite.17−20 The role of
crystals and their properties in the control of malaria have been
invoked, however, during investigations aimed at antimalarial
drugs that can prevent the crystallization of hemozoin, which
forms in the food vacuole of the Plasmodium falciparum
parasite from free heme generated when the parasite degrades
hemoglobin. In this manner, the crystallization of the very
insoluble hemozoin effectively removes the parent heme,
which otherwise would be toxic to the parasite.21−25
An alternative approach using solid-state chemistry is
considered here. DDT and DFDT are contact insecticides
that kill when insects directly contact the solid, but this
interaction had not been articulated in the context of solid-
state chemistry until the serendipitous discovery in our
laboratory of a second crystalline form of DDT (hence
designated as Form II) that killed Drosophila (the fruit fly)
more quickly than the only form (now Form I) previously
identified.26 This suggested a pathway to faster-acting agents
based on engineering of solid-state forms that could slow
resistance development because of their faster action. More-
over, improved efficacy means that smaller quantities are
required to achieve the same effect, promising a reduction in
environmental impact. New insecticides are urgently needed as
mosquitoes worldwide are becoming resistant to pyrethroids
embedded in long lasting insecticidal nets (LLINs), threat-
ening gains against malaria.27 Herein we demonstrate that
newly discovered solid-state forms of DFDT and its chiral
mono-fluoro analog MFDT28 (1,1,1-trichloro-2,2-(4-chloro-
phenyl)-(4-fluorophenyl)-ethane; Figure 1a) act much more
rapidly than DDT against Drosophila as well as Anopheles
quadrimaculatus, a vector for malaria, and Aedes aegypti, a
vector for Zika virus, yellow fever, dengue, and chikungunya.29
These results also demonstrate an unambiguous link between
thermodynamic stability and knockdown speed for important
disease vectors, suggesting that manipulation of the solid-state
chemistry of contact insecticides is a viable strategy for
mitigating insect-borne diseases, with an accompanying benefit
of reducing environmental impact.
RESULTS AND DISCUSSION
■
DFDT and MFDT were synthesized from trichloroacetate and
p-fluorobenzaldehyde to give 1-(4-fluorophenyl)-2,2,2-trichlor-
oethanol.30 Subsequent reaction with fluorobenzene or
chlorobenzene afforded DFDT and MFDT, respectively.31
Two polymorphic crystalline forms of DFDT (DFDT-I, -II)
and three polymorphic forms of racemic MFDT ((RS)-
MFDT-I, -II, and -III) were discovered (see Experimental
Section and Supporting Information, Figures S1−S4). DFDT-I
single crystals could be obtained from a variety of solvents and
DFDT-II single crystals from diethyl ether. (RS)-MFDT-I
could be crystallized from a variety of solvents. The (R)- and
(S)-MFDT enantiomers were resolved by chromatography on
a chiral stationary phase (Supporting Information, Figure S6),
and single crystals were grown from a variety of solvents.
B
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Figure 2. Lethalities of solid-state forms of DFDT, MFDT, and DDT for Drosophila melanogaster. (a−c) Each symbol corresponds to one female.
Dashed lines indicate logistic regression of knockdown-time curves. The median knockdown time for each curve is denoted by its intersection with
the horizontal KT50 marker. (d) Comparison of the knockdown speeds (1/KT50) relative to DDT I. Error bars represent 95% confidence intervals
(CI). Values with the same letter have overlapping 95% CIs, and differences are considered insignificant. Inset: Photo of a typical female fly.
Curiously, single crystals of (RS)-MFDT-II and -III were
obtained by crystallization from the melt at >30 and 25 °C,
respectively, using seed crystals of either the R or S isomer.
These crystalline forms, six total, were characterized by single-
crystal X-ray diffraction (Figure 1; Supporting Information,
Figure S7). The melting points of DFDT-I and -II were similar
(Tm = 40 and 39 °C, respectively; Supporting Information,
Figure S8) but microcrystalline DFDT-II slowly transformed
to DFDT-I at room temperature (Supporting Information,
Figures S9−S11), indicating that the latter is more
thermodynamically stable. (RS)-MFDT-II and -III micro-
crystals slowly transformed to (RS)-MFDT-I at room temper-
ature (Supporting Information, Figures S12−S14), although
III transformed much more rapidly. The apparent thermody-
namic stabilities of crystalline MFDT racemates parallel their
melting points, Tm: RS-I (62 °C) > RS-II (54 °C) > RS-III (35
°C) (Supporting Information, Figure S8). Collectively, this is
strong evidence (RS)-MFDT-III is less stable than its Form II
at room temperature, especially given the low melting point of
Form III. The Tm of the enantiomorphs was 47 °C
(Supporting Information, Figure S8). Amorphous DFDT (a-
DFDT), prepared by supercooling melts or fine mist spraying
of solutions (Supporting Information, Table S3), afforded
broad X-ray scattering halos (Figure 1h; Supporting
Information, Figure S2), and was stable for 25 days at room
temperature. Amorphous resolved and racemic MFDT (a-(R)-
and a-(S)-MFDT, and a-(RS)-MFDT, respectively; Figure 1h)
were stable for 10 days at room temperature. These
observations contrast with a-DDT, which transformed to
crystalline DDT Form I within 5 h at room temperature.
Notably, a-DFDT is stable for at least 120 days by addition of
10 wt% PEG 100 emulsifier, promising its use as a contact
insecticide.
Female Drosophila melanogaster were exposed to 2.0 0.1
mg of DFDT, MFDT, and DDT separately, in their crystalline
and amorphous forms (Supporting Information, Figure S15).
The insects were monitored with a video camera until the
entire population ceased to move. The videos then were
analyzed to determine the knockdown timesa proxy for
lethalityfor each individual insect (Videos S1−S5).32 Like
DDT, DFDT and MFDT induced hyperactivity followed by
paralysis, and then death. KT50 values, the times required for
death of 50% of the insects, are the standard for assessing
insecticide lethality (the lifetimes of individual insects differ
because of the random nature of their contact with insecticide
surfaces and varied susceptibility of a population). Here, the
KT50 values were calculated by logistic regression of knock-
down-time curves (Supporting Information, Figure S16, Table
S4).33 The KT50 values spanned the range of 261 to 54 min,
decreasing in the order DDT-I > DDT-II > (S)-MFDT >
(RS)-MFDT-I > DFDT-I ∼ (RS)-MFDT-II > (R)-MFDT ∼
(RS)-MFDT-III > a-(S)-MFDT ∼ DFDT-II > a-(RS)-MFDT
> a-(R)-MFDT > a-DFDT (Figure 2a−c; Supporting
Information, Figure S17). Knockdown speeds, reciprocals of
KT50 values,34 decreased in inverse order (Figure 2d). The
amorphous forms are always faster than their respective
crystalline counterparts, with a-DFDT the fastest. The MFDT
R forms, whether crystalline or amorphous, have higher
knockdown speeds than their respective S forms suggesting
enantioselectivity in uptake by the insect or neurotoxicity.
Overall, the lethalities of the different solid forms of a given
compound, as deduced from their knockdown speeds, were
inversely correlated with their thermodynamic stability.26,35
Female Anopheles and Aedes mosquitoes exposed to 1.0
0.1 mg of various crystalline forms followed the same
knockdown trend as Drosophila, with KT50 values decreasing
in the order DDT-I > (RS)-MFDT-I > DFDT-I > DFDT-II
C
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Figure 3. (a, b) Lethalities of crystalline forms of DFDT, (RS)-MFDT, and DDT for Anopheles quadrimaculatus (a) and Aedes aegypti (b). (c−e)
Lethalities of amorphous forms a-DFDT, a-(RS)-MFDT, and a-DDT for Anopheles quadrimaculatus (c), Aedes aegypti (d), and Drosophila
melanogaster (e). Each symbol corresponds to one female. Dashed lines indicate logistic regression of knockdown-time curves. The median
knockdown time for each curve is denoted by its intersection with the horizontal KT50 marker. (f) Relative knockdown speeds of amorphs. Error
bars represent 95% confidence intervals (CI). Values with the same letter have overlapping 95% CIs, and differences are considered insignificant.
Insets: Photos of typical females.
(Figure 3a,b; Videos S6 and S7). Given that DFDT and
MFDT amorphs were more active than their crystalline forms
against Drosophila, the lethalities of the amorphous forms were
evaluated as well for Anopheles and Aedes mosquitoes. Female
mosquitoes were introduced into Petri dishes coated with 1.0
0.1 mg of the amorphous forms, and their motions recorded
(Videos S8−S10). KT50 values for a-DFDT and a-(RS)-MFDT
against Anopheles were 29 and 39 min, and against Aedes they
were 30 and 40 min, respectively (Figure 3 c,d; Supporting
Information, Figure S20). Corresponding KT50 values for a-
DDT were much larger (120 and 112 min). Accordingly, the
knockdown speeds for a-DFDT and a-(RS)-MFDT are 4 and 3
times faster than for a-DDT, respectively (Figure 3f).
concerns, requiring Aedes control. Insecticide knockdown
speed is paramount to thwart mosquitoes surviving contact
and then reproducing. DFDT and MDFT may be alternatives
to compounds currently used for indoor residual spraying
malaria prevention among other diseases.16 The environmental
impacts of these compounds have not been evaluated, but in
this context they should be considered as different
compositions of matter, free of the DDT stigma. Furthermore,
the various solid forms of these new compositions exhibit
different activities for the demise of Drosophilia as well as
Anopheles and Aedes, demonstrating that manipulation of solid-
state structure is a viable strategy for the design of more
effective contact insecticides for mitigating insect-borne
diseases, with an accompanying benefit of reducing environ-
mental impact.
CONCLUSIONS
■
DFDT was last manufactured in 1945. Allied military
investigators, on discovering the pest control techniques of the
German armed forces, were derisive. “The German claims as to
In a warming world, the range of Anopheles mosquitoes may
increase.36 Meanwhile, the spread of Zika virus37,38 and
outbreaks of yellow fever39 have become severe public health
D
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grinding (R)-MFDT crystals grown from dichloromethane solutions,
were pure (R)-MFDT by PXRD. Microcrystals of (S)-MFDT,
prepared by grinding (S)-MFDT crystals grown from dichloro-
methane solutions, were pure (S)-MFDT by PXRD. Microcrystals of
DDT-I, prepared by grinding commercially obtained DDT crystals
(Sigma-Aldrich), were pure DDT-I by PXRD. DDT-II was prepared
by evaporation, under room conditions, of a 5 wt% DDT-methyl
propionate solution on a glass slide, which produced a crystalline
DDT film. The film was then scraped from the slide to give
microcrystals containing 60% DDT-II and 40% DDT-I, by PXRD.
Amorphous forms of DFDT, (RS)-MFDT, (R)-MFDT, (S)-MFDT,
and DDT were prepared by fine mist spraying of their respective
hexane solutions onto the top and bottom of 10.0 cm polystyrene
Petri dishes, followed by evaporation of hexane, resulting in the
amorphous insecticides on both surfaces.
Lethality Measurements for Amorphous and Crystalline
Insecticides. The lethality of solid-state forms of insecticides was
determined by the residual exposure method. Each crystalline form
was ground to a particle size similar to that of the amorphous particles
prepared by fine mist spraying (Supporting Information, Figure S15).
Lethality measurements were performed in duplicate for each solid-
state form, each accompanied by two controls (no insecticide). Each
microcrystalline form was added to a 10 cm diameter polystyrene
Petri dish (2.0 mg per dish for fruit flies, 1.0 mg per dish for
mosquitos), which was subsequently shaken to disperse the
microcrystals throughout the Petri dish. Amorphous forms were
prepared by fine mist spraying a stock solution containing 70 or 35
mg of the respective insecticide in 10 mL hexane onto the top and
bottom of 10 cm diameter polystyrene Petri dishes (two sprays =
0.280 mL) and allowing the hexane to evaporate at room temperature,
resulting in 2.0 or 1.0 mg of amorphous insecticide in each Petri dish.
Adults mosquitos (Anopheles quadrimaculatus or Aedes aegypti) or fruit
flies (Drosophila melanogaster) were sedated with carbon dioxide and
25 female mosquitos or flies were transferred to each Petri dish. The
top of the dish was then placed over the bottom, and the motion of
the mosquitos or fruit flies was recorded with a video camera (Sony
HDR-CX455). The knockdown time was measured for each
individual insect, with knockdown associated with an insect laying
on the bottom surface of the Petri dish in a supine position without
moving from its original position after 10 s.
the superior insecticidal action of DFDT in comparison to
DDT”, reads a military intelligence report, “are not clearly
supported by their meager and inadequate tests against
houseflies.”40 German credibility in the use of chemical
insecticides could not have been lower given the revelations
coming from Eastern Europe. The results herein show that
DFDT claims were credible and that fluorine substitution for
para-chlorine atoms in DDT markedly speeds the action of
DFDT and MFDT by comparison. This may be considered in
vector control strategies of the near future that can no longer
rely solely on pyrethroids. A German “silent spring”, der
stumme Fruhling, the consequence of the overuse of DFDT if
̈
Germany had won the war in Europe, would have been a
different story, but one that cannot be imagined at present in
the absence of knowing the environmental consequences of the
fluorine-substituted congeners, risks that warrant further
investigation.
EXPERIMENTAL SECTION
■
Crystallization of Single Crystals of DFDT-I and -II. Single
crystals of DFDT in various crystalline forms were prepared in 20 mL
glass vials by slow evaporation from a variety of solutions, listed in
Supporting Information, Table S1. Single crystals of DFDT-I for X-ray
analysis were prepared by placing small single crystal seeds of DFDT-I
in contact with a supercooled melt of DFDT, then heating the melt at
40 °C on a hot stage for 7 days. DFDT-II single crystals for X-ray
analysis were prepared in a 20 mL glass vial by slow evaporation from
diethyl ether solutions.
Crystallization of Single Crystals of (R)-MFDT and (S)-MFDT.
Single crystals of (R)-MFDT for X-ray analysis were prepared by
placing small single crystal seeds of (R)-MFDT in contact with a
supercooled melt of (R)-MFDT, then heating the melt at 50 °C on a
hot stage for 2 days. Single crystals of (S)-MFDT for X-ray analysis
were prepared in the same way as single crystals of (R)-MFDT.
Crystallization of Single Crystals of (RS)-MFDT-I, -II, and -III.
The (RS)-MFDT-I single crystals for X-ray analysis were prepared in
a 20 mL glass vial by slow evaporation from dichloromethane
solutions. Heterogeneous nucleation of (RS)-MFDT-II and (RS)-
MFDT-III crystals were induced by placing single crystals of (R)-
MFDT or (S)-MFDT in contact with supercooled melt of (RS)-
MFDT at 30−50 °C and room temperature, respectively. The (RS)-
MFDT-II single crystals for X-ray analysis were prepared by placing
small single crystal seeds of (S)-MFDT in contact with a supercooled
melt of (RS)-MFDT, which was then heated at 35 °C for 2 weeks.
The (RS)-MFDT-III single crystals for X-ray analysis were prepared
by placing small single crystal seeds of (S)-MFDT in contact with a
supercooled melt of (RS)-MFDT, which was then allowed to stand at
room temperature for 1 day.
Statistical Analyses. Logistic regression of knockdown-time
curves was preformed to obtain the median knockdown time
(KT50) of the test flies and mosquitoes, the 95% confidence intervals
(CI), slopes, and standard errors (SE) using Qcal software.33
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b08125.
■
S
Raman spectra of solid-state forms; powder X-ray
diffraction patterns; growth of (RS)-MFDT-II and -III
by seeded nucleation; single crystals with Miller indices;
preparation of DFDT and MFDT crystals; elution data
for chiral resolution of (RS)-MFDT; crystal structure of
(RS)-MFDT-II and selected crystal data for DFDT-I and
-II, (RS)-MFDT-I, -II, and -III, (R)-MFDT, and (S)-
MFDT; differential scanning calorimetry; polymorphic
compositions; timeline of the % transformation of
polymorphs; powder X-ray diffraction patterns of
DFDT-II microcrystals during transformation to
DFDT-I; preparation of amorphous DFDT and
MFDT by fine mist spraying; particles of solid-state
forms of DFDT, MFDT, and DDT used for lethality
measurements; logistic regression of knockdown-time
curves for D. melanogaster exposed to solid-state forms of
DFDT, MFDT, and DDT; parameters obtained from
logistic regression of knockdown-time curves for D.
Preparation of the Amorphous State of DFDT, (RS)-MFDT,
(R)-MFDT, (S)-MFDT, and DDT. The amorphous states of
insecticides were prepared by fine mist spraying of a variety of
solutions, listed in Supporting Information, Table S2.
Preparation of Samples in Different Solid-State Forms for
Lethality Measurements. Microcrystals of DFDT-I, prepared by
grinding DFDT-I crystals, grown from hexane solutions, using a
mortar and pestle, were DFDT-I by powder X-ray diffraction
(PXRD). Microcrystals of DFDT-II, prepared by grinding the
DFDT-II crystals grown from diethyl ether solutions, contained
93% DFDT-II and 7% DFDT-I by PXRD. Microcrystals of (RS)-
MFDT-I, prepared by grinding (RS)-MFDT-I crystals grown from
dichloromethane solutions, were pure (RS)-MFDT-I by PXRD.
Microcrystals of (RS)-MFDT-II, prepared by grinding the (RS)-
MFDT-II crystals grown from the melt, contained a small amount of
(RS)-MFDT-I (94% (RS)-MFDT-II and 6% (RS)-MFDT-I) by
PXRD. Microcrystals of (RS)-MFDT-III, prepared by grinding the
(RS)-MFDT-III crystals grown from the melt, contained a small
amount of (RS)-MFDT-I (96% (RS)-MFDT-III and 4% (RS)-
MFDT-I) by PXRD. Microcrystals of (R)-MFDT, prepared by
E
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(2) Simon, C. DDT: Kulturgeschichte einer Chemischen Verbindung;
Christoph Merian Verlag: Basel, 1999.
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melanogaster; median knockdown times of lethality of D.
melanogaster; lethality measurements of vapor of DFDT,
(RS)-MFDT, and DDT for D. melanogaster; median
knockdown times of lethality measurements of amor-
phous DFDT, (RS)-MFDT, and DDT against D.
melanogaster, A. quadrimaculatus, and Ae. aegypti; NMR
spectra; and molecular structures depicted as ellipsoids
in 50% probability (PDF)
X-ray crystallographic data for DFDT-I and -II, (RS)-
MFDT-I, -II and -III, (R)-MFDT, and (S)-MFDT
(CIF)
Video S1, lethality measurements of amorphous DFDT,
DFDT-I, and DFDT-II microcrystals for D. melanogaster
(MP4)
Video S2, lethality measurements of amorphous (R)-
MFDT, (RS)-MFDT, and (S)-MFDT for D. melanogast-
er (MP4)
Video S3, lethality measurements of (R)-MFDT, (RS)-
MFDT-I, and (S)-MFDT microcrystals for D. mela-
nogaster (MP4)
Video S4, lethality measurements of (RS)-MFDT-II and
-III microcrystals for D. melanogaster (MP4)
Video S5, lethality measurements of DDT-I and -II
microcrystals for D. melanogaster (MP4)
Video S6, lethality measurements of DFDT-I and -II,
(RS)-MFDT-I, and DDT-I microcrystals for A. quad-
rimaculatus (MP4)
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Video S7, lethality measurements of DFDT-I and -II,
(RS)-MFDT-I, and DDT-I microcrystals for Ae. aegypti
(MP4)
(17) Li, H.; Tsu, C.; Blackburn, C.; Li, G.; Hales, P.; Dick, L.;
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Video S8, lethality measurements of amorphous DFDT,
(RS)-MFDT, and DDT for D. melanogaster(MP4)
Video S9, lethality measurements of amorphous DFDT,
(RS)-MFDT, and DDT for A. quadrimaculatus (MP4)
Video S10, lethality measurements of amorphous
DFDT, (RS)-MFDT, and DDT for A. aegypti (MP4)
(18) Yoo, E.; Stokes, B. H.; de Jong, H.; Vanaerschot, M.; Kumar, T.
R. S.; Lawrence, N.; Njoroge, M.; Garcia, A.; Van der Westhuyzen, R.;
Momper, J. D.; Ng, C. L.; Fidock, D. A.; Bogyo, M. Defining the
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AUTHOR INFORMATION
■
(19) Zhao, Y.; Chen, Z.; Chen, Y.; Xu, J.; Li, J.; Jiang, X. Synergy of
Non-antibiotic Drugs and Pyrimidinethiol on Gold Nanoparticles
against Superbugs. J. Am. Chem. Soc. 2013, 135, 12940−12943.
Corresponding Authors
*mdw3@nyu.edu
*bart.kahr@nyu.edu
̈
(20) Tyler, P. C.; Taylor, E. A.; Frohlich, R. F. G.; Schramm, V. L.
ORCID
Synthesis of 5′-Methylthio Coformycins: Specific Inhibitors for
Malarial Adenosine Deaminase. J. Am. Chem. Soc. 2007, 129, 6872−
6879.
Chunhua T. Hu: 0000-0002-8172-2202
Jingxiang Yang: 0000-0002-0859-6668
Leo A. Joyce: 0000-0002-8649-4894
Michael D. Ward: 0000-0002-2090-781X
Bart Kahr: 0000-0002-7005-4464
(21) Bohle, D. S.; Debrunner, P.; Jordan, P. A.; Madsen, S. K.;
Schulz, C. E. Aggregated Heme Detoxification Byproducts in Malarial
Trophozoites: β-Hematin and Malaria Pigment have a Single S = 5/2
Iron Environment in the Bulk Phase as Determined by EPR and
Notes
̈
Magnetic Mossbauer Spectroscopy. J. Am. Chem. Soc. 1998, 120,
8255−8256.
The authors declare no competing financial interest.
(22) Solomonov, I.; Osipova, M.; Feldman, Y.; Baehtz, C.; Kjaer, K.;
Robinson, I. K.; Webster, G. T.; McNaughton, D.; Wood, B. R.;
Weissbuch, I.; Leiserowitz, L. Crystal Nucleation, Growth, and
Morphology of the Synthetic Malaria Pigment β-Hematin and the
Effect Thereon by Quinoline Additives: The Malaria Pigment as a
Target of Various Antimalarial Drugs. J. Am. Chem. Soc. 2007, 129,
2615−2627.
(23) Olafson, K. N.; Clark, R. J.; Vekilov, P. G.; Palmer, J. C.; Rimer,
J. D. Structuring of Organic Solvents at Solid Interfaces and
Ramifications for Antimalarial Adsorption on β-Hematin Crystals.
ACS Appl. Mater. Interfaces 2018, 10, 29288−29298.
(24) Fitzroy, S.-M.; Gildenhuys, J.; Olivier, T.; Tshililo, N. O.; Kuter,
D.; de Villiers, K. A. The Effects of Quinoline and Non-Quinoline
ACKNOWLEDGMENTS
■
This work was primarily supported by the New York
University Materials Research Science and Engineering Center
(MRSEC) program of the National Science Foundation under
award number DMR-1420073. The NYU X-ray facility is
supported partially by the NSF under Award Number CRIF/
CHE-0840277.
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