Escaping from Flatland: Antimalarial Activity of sp3-Rich Bridged Pyrrolidine Derivatives

Article abstract of DOI:10.1021/acsmedchemlett.0c00486

We utilized synthetic photochemistry to generate novel sp3-rich scaffolds and report the design, synthesis, and biological testing of a diverse series of amides based on the 1-(amino-methyl)-2-benzyl-2-aza-bicyclo[2.1.1]hexane scaffold. Preliminary antimalarial screening of the library provided promising compounds with activity in the 1-5 μM range with an enhanced hit rate. Further evaluation (solubility, drug metabolism and pharmacokinetics (DMPK), and toxicity) of a selected compound (9) suggested that this series represents an excellent opportunity for further optimization with the framework offering multiple opportunities for the addition of uniquely vectorally positioned extra functionality.

Full text of DOI:10.1021/acsmedchemlett.0c00486

pubs.acs.org/acsmedchemlett
Letter
Escaping from Flatland: Antimalarial Activity of sp3‑Rich Bridged
Pyrrolidine Derivatives
Brian Cox,* James Duffy, Victor Zdorichenko, Corentin Bellanger, Jessica Hurcum, Benoît Laleu,
Kevin I. Booker-Milburn, Luke D. Elliott, Michael Robertson-Ralph, Christopher J. Swain,
Stephen J. Bishop, Irene Hallyburton, and Mark Anderson
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ABSTRACT: We utilized synthetic photochemistry to generate novel sp3-rich scaffolds and report the design,
synthesis, and biological testing of a diverse series of amides based on the 1-(amino-methyl)-2-benzyl-2-aza-
bicyclo[2.1.1]hexane scaffold. Preliminary antimalarial screening of the library provided promising compounds
with activity in the 1−5 μM range with an enhanced hit rate. Further evaluation (solubility, drug metabolism
and pharmacokinetics (DMPK), and toxicity) of a selected compound (9) suggested that this series represents
an excellent opportunity for further optimization with the framework offering multiple opportunities for the
addition of uniquely vectorally positioned extra functionality.
KEYWORDS: Drug discovery, antimalarial, photochemistry, sp3-rich substituted bridged pyrrolidines, 3D character
alaria is an infectious disease transmitted by mosquitoes
Minfected with five species of single-celled eukaryotic
Plasmodium parasites (most commonly Plasmodium falciparum
and Plasmodium vivax). In 2018, there were an estimated 228
million cases of malaria globally, with half of the world’s
population at risk. Malaria transmission continues to affect
more than 90 countries and territories around the world,
inflicting a tremendous burden in sub-Saharan Africa with
more than 90% of cases on the African continent. In 2018,
malaria was estimated to cause 405,000 deaths, 99% of which
are due to P. falciparum in Africa. Parasite resistance against
currently recommended artemisinin-based combination thera-
pies (ACTs) is a major concern, and new antimalarial drugs
with novel modes of action are urgently needed as well as
drugs that interrupt the parasite life cycle by blocking
transmission to the vectors, prevent infection, and target
malaria species that transiently remain dormant in the liver.1,2
Finding new medicines for malaria has proven to be
challenging; part of this stems from the difficulty of identifying
molecules from screening that are tractable and novel starting
points. The hit rate found when screening conventional
chemical libraries, which also contain compounds with known
antimicrobial motifs, has been reported to be 0.4−1%;3
however two recent screens carried out by Medicines for
Malaria on libraries with compounds with known antimicrobial
motifs excluded showed much lower hit rates of 0.07% and
0.09% respectively (hit defined as compound with IC50 > 2
μM). Clemons et al. examined compounds from different
sources (commercial, research, natural) for their protein-
binding behaviors and found that these correlate with general
trends in stereochemical and shape descriptors for these
compound collections. Increasing the content of sp3-hybridized
and stereogenic centers in novel compounds improved binding
selectivity and most importantly hit frequency.4 This was in
contrast to those from commercial sources, which generally
comprise the majority of current screening collections.
We were prompted to look at synthetic methodologies that
could be used to efficiently generate novel, complex, sp3-rich
frameworks that could be utilized in the generation of a
number of novel libraries to undergo screening for antimalarial
activity. For the past five years, we have been investigating the
use of photochemistry, in particular [2 + 2] cycloadditions, to
produce novel chemical entities as desirable starting points for
drug discovery.5,6
Apart from the apparent positive impact on hit finding,
another key importance of sp3-enrichment was highlighted by
Lovering et al.,7 who utilized fraction sp3 (Fsp3) where Fsp3 =
(number of sp3 hybridized carbons/total carbon count) as a
simple and interpretable measurement of the complexity of
molecules. They were able to show that complexity (as
measured by Fsp3) appears to correlate with the chance of
success of compounds transitioning from discovery through
clinical testing to marketed drugs. They also demonstrated that
increased saturation generally correlated with improved
solubility, an often a desirable property for a drug.7 In later
work, Lovering described how increasing complexity reduces
promiscuity and CYP450 enzyme inhibition, with increased
promiscuity being linked to toxicity and ultimately to failure.8
Received: September 4, 2020
Accepted: November 5, 2020
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With these influences in mind, we set out to design a novel
sp3-rich screening library and demonstrate its utility by
identifying novel antimalarial leads. As previously reported,
we have focused some of our efforts on analogues and
derivatives of 2,4-methanoproline 1 (Figure 1).6 For this effort,
Scheme 2. Synthesis of 1-(Amino-methyl)-2-benzyl-2-aza-
bicyclo[2.1.1]hexane 2a
a
a
Reagents and conditions: (a) LiAlH4, THF (78%); (b) phthalimide,
polymer-supported PPh3, DIAD, THF (83%); (c) H2NNH2, EtOH
(72%); (d) DIPEA, HATU, DCM, R1 carboxylic acid or DIPEA,
COMU, DCM, R1 carboxylic acid (See Table 1 for yields).
A diverse 234-member array of amide derivatives of 2a was
then prepared using a parallel synthesis/purification method
employing standard amide forming reactions with HATU or
COMU as coupling agents. (See Supporting Information for a
full list of the compounds synthesized).
The compounds were assessed for their antimalarial activity
using a 3D7 SYBR Green I in vitro assay.15,16 All compounds
were screened in a single point assay at a concentration of 10
μM to identify those with activity >50% inhibition. Actives and
a representative selection of less active compounds were
screened in potency mode with a top concentration of 25 μM
following a 10-point 1 in 3 dilution series (see Table 1; see
Supporting Information for a full list of the screening data for
the compounds synthesized).
The 68 compounds titrated displayed IC50 values in the
range 1 to 25 μM with a reasonable correlation between the
activity in the primary assay and the titrated IC50 assay (Figure
2). Three compounds have activity <2 μM providing a hit rate
of 1.3% based on this cut off, which compares extremely
favorably with the hit rates of the two recent screens described
earlier.
Figure 1. Proline analogues.
we selected 1-(amino-methyl)-2-benzyl-2-aza-bicyclo[2.1.1]-
hexane 2a as an ideal key scaffold for the preparation of the
library. During the completion of the work in this publication,
2a was reported by Levterov et al. as a precursor to the two
differentially protected N-Boc derivatives 2b and 2c.9 Although
there have been numerous reports of the “aminoproline” 3, its
analogues, and their biological activities, there are relatively few
reports of biological activity associated with the 2,4-methano-
bridged variant. Two examples are the insect repellent/
antifeedant activity of compounds such as 2d10 and the
potential therapeutic application of compounds such as 4,
found to be potent inhibitors of the glycine transporter
GlyT1.11
The N-benzoyl ethyl ester of 2,4-methanoproline 5 was
prepared by the method of Malpass et al. in a two step process
from ethyl pyruvate (Scheme 1) via an intramolecular [2 + 2]
Scheme 1. Synthesis of Ethyl 2-Benzoyl-2-
azabicyclo[2.1.1]hexane-1-carboxylate 5
a
The unsubstituted benzamide (203) was found to be
inactive (−20% @ 10 μM); however, positioning a chloro at
the 3-position of the phenyl ring gave useful activity (51, IC50
13 μM). The bioisosteric 3-bromo (89, 35% @ 10 μM) and 3-
methyl (109, 7.6% @ 10 μM) analogues showed no advantage.
However, the 3-trifluoromethoxy (38, IC50 9.3 μM) showed a
possible improvement. The 2-chloro (143, −7.9% @ 10 μM)
and 4-chloro (81, 38% @ 10 μM) proved to be less active.
Using the 3-chloro as the starting point for further analysis,
additional substitution at the 2-position (e.g., the 2,3-dichloro
compound 147, −8.2% @ 10 μM) and the 6-position (e.g., the
3-chloro-6-methyl analogue 62, IC50 19 μM) proved
detrimental. In contrast, 3,4-disubstitution offered a modest
improvement in activity (21, IC50 5.1 μM). Additional
substitution at the 5-position proved to be the most
advantageous (e.g., the 3-chloro-5-trifluoromethyl analogue 9,
IC50 1.3 μM). A range of derivatives with lipophilic
substituents in the 3,5-positions were also active. In general,
the analogous benzylamides were less active (see 43 vs 21, 67
vs 42, 80, vs 46, and 146 vs 72); however substitution at the
benzylic position dramatically improved activity with the
spirocyclobutyl compound 26 (IC50 6.2 μM) proving to be
a
Reagents and conditions: (a) allylamine then PhCOCl, Et3N,
toluene (47%); (b) hν, acetone (40%).
olefin photocycloaddition reaction.12 The original syntheses of
the N-benzoyl methyl ester of 2,4-methanoproline were
published in back-to-back articles, the first utilizing the methyl
pyruvate13 and the second starting from serine.14
The N-benzoyl ethyl ester of 2,4-methanoproline 5 was used
to prepare 2a in a three stage process (Scheme 2); first
reduction with lithium aluminum hydride to produce the N-
benzyl alcohol 6, followed by a Mitsunobu reaction with
phthalimide to generate the phthalimide derivative 7, and
finally hydrazinolysis to yield the desired material. Levterov et
al. used an alternative approach via the tosylate of 6, followed
by conversion to the azide and then Staudinger reduction.9
B
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Table 1. Antimalarial Activities of Amide Derivatives of 1-(Amino-methyl)-2-benzyl-2-aza-bicyclo[2.1.1]hexane 2a in the 3D7
SYBR Green I In Vitro Assay
C
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Table 1. continued
active, and impressively the spirocyclopropyl compound 8
(IC50 1.1 μM) proved to be the most active in the library. In a
further trend, the fluorostyryl compounds 44, 65, and 52 all
proved to be more active than their benzyl or phenyl
counterparts (where prepared). In general, heterocyclic amides
are not well tolerated, the exception being the isoxazole (14,
IC50 3.4 μM).
A range of physicochemical properties were calculated using
a Jupyter notebook17 and ChemAxon tools. In general, the
compounds conform to the “rule of five” definition of drug-
likeness with log P < 5 and molecular weight <500. In terms of
D
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Figure 3. Spacial comparison of pyrrole, pyrrolidine, and azabicycle
cores.
Table 2. Comparison of the Normalized Principle Moments
of Inertia (NPR) and Plane of Best Fit (PBF) of Pyrrole,
Pyrrolidine, and Azabicycle Cores
structure
NPR1
NPR2
∑NPR
PBF
pyrrole
pyrrolidine
azabicycle
0.22
0.32
0.36
0.84
0.86
0.91
1.06
1.18
1.27
0.58
0.70
0.83
Figure 2. Plot of % inhibition in the primary assay at 10 μM and
titrated IC50 value (μM).
ionization, the majority are predicted to be basic and
protonated at physiological pH, albeit with a range of pKa
from 7.2 to 8.4. Early profiling data received for 9 confirmed
this with a log D = 3.2, and kinetic solubility >200 μM. Early
DMPK and toxicity profiling further indicated its value as an
early lead candidate (HLM CLint = 27 μL·min−1·mg−1 and
RHeps CLint = 8 μL·min−1·(106 cells)−1) and an IC50 in a Hep
G2 cell assay of >17 μM (the maximum concentration of the
assay). The compound was also assessed against the multiple
drug resistant strain Dd2 in an LDH format assay alongside the
nonresistant 3D7 strain. Excitingly, the compound was found
to have similar activities against both strains (Dd2 IC50 5.4 μM
and 3D7 IC50 4.3 μM).
ought to provide highly desirable templates. Here we have
shown that the 2,4-methanoproline derived template provided
a unique library with an enhanced hit rate, good drug-like
properties, and a viable starting point for further optimization
in an antimalarial program.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00486.
■
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Synthetic methods, characterization, biological assay
methods and results, and crystallographic and computa-
tional modeling data (PDF)
The ChEMBL Neglected and Tropical Disease Archive18
contains a number of data sets of screening and medicinal
chemistry campaigns directed toward NTD targets including
malaria. These data sets were imported into Vortex, InChiKeys
were generated and a script was run comparing InChiKeys for
all compounds. While there is considerable overlap between
some of the ChEMBL data sets, none of the photodiversity
compounds were present in any of the previously tested data
sets.
Comparison of the “bridged” azabicyclic framework with
that of the pyrrole and pyrrolidine (one enantiomer selected)
analogues shows that the framework offers many more
divergent vectors for further elaboration and thus exploration
of 3D space (Figure 3).19
AUTHOR INFORMATION
Corresponding Author
■
Brian Cox − School of Life Sciences and Photodiversity Ltd, c/
o School of Life Sciences, University of Sussex, Brighton BN1
9QJ, U.K.; orcid.org/0000-0002-5980-9707;
Email: b.cox@sussex.ac.uk, contact@
photodiversity.uk.com
Authors
James Duffy − Medicines for Malaria Venture, 1215 Geneva
15, Switzerland
Victor Zdorichenko − Photodiversity Ltd, c/o School of Life
Sciences, University of Sussex, Brighton BN1 9QJ, U.K.
Corentin Bellanger − Photodiversity Ltd, c/o School of Life
Sciences, University of Sussex, Brighton BN1 9QJ, U.K.
Jessica Hurcum − School of Life Sciences, University of Sussex,
Brighton BN1 9QJ, U.K.
Benoît Laleu − Medicines for Malaria Venture, 1215 Geneva
15, Switzerland; orcid.org/0000-0002-7530-2113
Kevin I. Booker-Milburn − School of Chemistry and
Photodiversity Ltd, c/o School of Chemistry, University of
Bristol, Bristol BS8 1TS, U.K.; orcid.org/0000-0001-
6789-6882
As in our previous publication,6 further analysis was carried
out to assess relative shape across these three frameworks using
principle moments of inertia (PMI)20 and plane of best fit
(PBF).21 These data are tabulated below (Table 2) and are
consistent with the suggestion that the azabicycle occupies an
area of chemical space described as more “three-dimensional”
(note that compounds with ∑NPR (sum of NPR1 and NPR2)
≥ 1.07 and PBF scores ≥ 0.6 are deemed by Firth et al. to
reside in 3D space).20
In conclusion, as researchers seek greater novelty and sp3
content in their screening sets, photocycloaddition reactions
E
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molecules of different origins have distinct distributions of structural
complexity that correlate with protein-binding profiles. Proc. Natl.
Acad. Sci. U. S. A. 2010, 107, 18787−18792.
Luke D. Elliott − School of Chemistry, University of Bristol,
Bristol BS8 1TS, U.K.
Michael Robertson-Ralph − Photodiversity Ltd, c/o School of
Chemistry, University of Bristol, Bristol BS8 1TS, U.K.
Christopher J. Swain − Cambridge MedChem Consulting,
CB22 4RN Cambridge, U.K.
Stephen J. Bishop − Photodiversity Ltd, c/o School of Life
Sciences, University of Sussex, Brighton BN1 9QJ, U.K.
Irene Hallyburton − Drug Discovery Unit, Wellcome Centre
for Anti-infective Research, University of Dundee, Dundee
DD1 5EH, U.K.
Mark Anderson − Drug Discovery Unit, Wellcome Centre for
Anti-infective Research, University of Dundee, Dundee DD1
5EH, U.K.
(5) Cox, B.; Booker-Milburn, K. I.; Elliott, L. D.; Robertson-Ralph,
M.; Zdorichenko, V. Escaping from flatland: [2 + 2] photo-
cycloaddition; conformationally constrained sp3-rich scaffolds for
lead generation. ACS Med. Chem. Lett. 2019, 10, 1512−1517.
(6) Cox, B.; Zdorichenko, V.; Cox, P. B.; Booker-Milburn, K. I.;
Paumier, R.; Elliott, L. D.; Robertson-Ralph, M.; Bloomfield, G.
Escaping from flatland: substituted bridged pyrrolidine fragments with
inherent three-dimensional character. ACS Med. Chem. Lett. 2020, 11,
1185−1190.
(7) Lovering, F.; Bikker, J.; Humblet, C. Escape from flatland:
increasing saturation as an approach to improving clinical success. J.
Med. Chem. 2009, 52, 6752−6756.
(8) Lovering, F. Escape from Flatland 2: complexity and
promiscuity. MedChemComm 2013, 4, 515−519.
(9) Levterov, V. V.; Michurin, O.; Borysko, P. O.; Zozulya, S.;
Sadkova, I. V.; Tolmachev, A. A.; Mykhailiuk, P. K. Photochemical in-
flow synthesis of 2,4-methanopyrrolidines: pyrrolidine analogues with
improved water solubility and reduced lipophilicity. J. Org. Chem.
2018, 83, 14350−14361.
(10) Stevens, C. V.; Smagghe, G.; Rammeloo, T.; De Kimpe, N.
Insect repellent/antifeedant activity of 2,4-methanoproline and
derivatives against a leaf- and seed-feeding pest insect. J. Agric. Food
Chem. 2005, 53, 1945−1948.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acsmedchemlett.0c00486
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Funding
We gratefully acknowledge support for Luke Elliott from the
Engineering and Physical Sciences Research Council (EP/
P013341/1).
(11) Dargazanli, G.; Estenne-Bouhtou, G.; Mafroud, A.-K. N-[(2-
azabicyclo[2.1.1]hex-1-yl)-aryl-methyl]-benzamide derivatives, prep-
aration thereof, and therapeutic use thereof. WO2010092286, August
19, 2010.
Notes
The authors declare the following competing financial
interest(s): B.C. and K.I.B.M. are employees of their respective
universities and cofounders and owners of Photodiversity Ltd.
J.D. and B.L. are employees of Medicines for Malaria Venture
(MMV).
(12) Malpass, J. R.; Patel, A. B.; Davies, J. W.; Fulford, S. Y.
Modification of 1-substituents in the 2-azabicyclo[2.1.1]hexane ring
system; approaches to potential nicotinic acetylcholine receptor
ligands from 2,4-methanoproline derivatives. J. Org. Chem. 2003, 68,
9348−9355.
(13) Pirrung, M. C. Total synthesis of 2,4-methanoproline.
Tetrahedron Lett. 1980, 21, 4577−4578.
ACKNOWLEDGMENTS
■
(14) Hughes, P.; Martin, M.; Clardy, J. Synthesis of 2,4-
methanoproline. Tetrahedron Lett. 1980, 21, 4579−4580.
The authors thank the following colleagues for providing small
molecule analysis data: Dr. Alaa Abdul-Sada (mass spectrom-
etry), Dr. Iain Day (NMR), and Dr. Mark Roe (X-ray
crystallography) at the University of Sussex. We also thank Dr.
Susanta Kumar of Mondal TCG Lifesciences Pvt Ltd, India, for
log D, kinetic solubility, LDH, and DMPK assays. We are also
grateful to the Universities of Sussex and Bristol.
(15) Baragana, B.; Hallyburton, I.; Lee, M. C. S.; Norcross, N. R.;
̃
Grimaldi, R.; Otto, T. D.; Proto, W. R.; Blagborough, A. M.; Meister,
S.; Wirjanata, G.; Ruecker, A.; Upton, L. M.; Abraham, T. S.; Almeida,
M. J.; Pradhan, A.; Porzelle, A.; Martínez, M. S.; Bolscher, J. M.;
Woodland, A.; Norval, S.; Zuccotto, F.; Thomas, J.; Simeons, F.;
Stojanovski, L.; Osuna-Cabello, M.; Brock, P. M.; Churcher, T. S.;
́
Sala, K. A.; Zakutansky, S. E.; Jimenez-Díaz, M. B.; Sanz, L. M.; Riley,
ABBREVIATIONS
J.; Basak, R.; Campbell, M.; Avery, V. M.; Sauerwein, R. W.;
Dechering, K. J.; Noviyanti, R.; Campo, B.; Frearson, J. A.; Angulo-
Barturen, I.; Ferrer-Bazaga, S.; Gamo, F. J.; Wyatt, P. G.; Leroy, D.;
Siegl, P.; Delves, M. J.; Kyle, D. E.; Wittlin, S.; Marfurt, J.; Price, R.
N.; Sinden, R. E.; Winzeler, E.; Charman, S. A.; Bebrevska, L.; Gray,
D. W.; Campbell, S.; Fairlamb, A. H.; Willis, P.; Rayner, J. C.; Fidock,
D. A.; Read, K. D.; Gilbert, I. H.; Luksch, T. A novel multiple-stage
antimalarial agent that inhibits protein synthesis. Nature 2015, 522
(7556), 315−320.
■
COMU, 1-cyano-2-ethoxy-2-oxoethylidenaminooxy)-
dimethylamino-morpholino-carbenium hexafluorophosphate;
CYP450, cytochrome P450; DCM, dichloromethane; DIAD,
diisopropyl azodicarboxylate; DIPEA, diisopropylethylamine;
DMPK, drug metabolism and pharmacokinetics; HATU, 1-
[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]-
pyridinium 3-oxide hexafluorophosphate; HLM, human liver
microsomes; THF, tetrahydrofuran
(16) Smilkstein, M.; Sriwilaijaroen, N.; Kelly, J. X.; Wilairat, P.;
Riscoe, M. Simple and inexpensive fluorescence-based technique for
high-throughput antimalarial drug screening. Antimicrob. Agents
Chemother. 2004, 48 (5), 1803−1806.
(17) Swain, C. J.; Macs in chemistry, physicochemical property profile
iPython notebook, https://www.macinchem.org/reviews/ipython/
calcproperties2.php (accessed Oct 13, 2020).
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