Medicinal Chemistry Optimization of a Diaminopurine Chemotype: Toward a Lead for Trypanosoma brucei Inhibitors

Article abstract of DOI:10.1021/acs.jmedchem.0c01017

Human African trypanosomiasis (HAT), or sleeping sickness, is caused by the protozoan parasite Trypanosoma brucei and transmitted through the bite of infected tsetse flies. The disease is considered fatal if left untreated. To identify new chemotypes against Trypanosoma brucei, previously we identified 797 potent kinase-targeting inhibitors grouped into 59 clusters plus 53 singleton compounds with at least 100-fold selectivity over HepG2 cells. From this set of hits, a cluster of diaminopurine-derived compounds was identified. Herein, we report our medicinal chemistry investigation involving the exploration of structure-activity and structure-property relationships around one of the high-throughput screening (HTS) hits, N2-(thiophen-3-yl)-N6-(2,2,2-trifluoroethyl)-9H-purine-2,6-diamine (1, NEU-1106). This work led to the identification of a potent lead compound (4aa, NEU-4854) with improved in vitro absorption, distribution, metabolism, and excretion (ADME) properties, which was progressed into proof-of-concept translation of in vitro antiparasitic activity to in vivo efficacy.

Full text of DOI:10.1021/acs.jmedchem.0c01017

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Article
Medicinal chemistry optimization of a diaminopurine
chemotype: Towards a lead for Trypanosoma brucei inhibitors
Baljinder Singh, Rosario Díaz González, Gloria Ceballos-Perez, Domingo
Isaac Rojas-Barros, Naresh Gunaganti, Kirsten Gillingwater, Maria Santos
Martínez-Martínez, Pilar Manzano, Miguel Navarro, and Michael P. Pollastri
J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.0c01017 • Publication Date (Web): 30 Jul 2020
Downloaded from pubs.acs.org on August 1, 2020
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C<BE S8(1, 6WT, B<-U S&, C m E<6 W3, -WT, 6<UU S?, C m E<] W3, -WT, 6<E]46<EX S:, 6WT, 6<ME46<M6 S:,
6WT< P7D) J0>%& BXX<MB uDsWvs, ?/ m 6<6X :$% SD'?+0& AT<
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S&, C m X<X W3, -WT, C<B6 S8(1, 6WT< P7D) J0>%& BXX<M uDsWvs ? m 6<-C :$% SD'?+0& AT<
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Page 23 of 40
Journal of Medicinal Chemistry
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:<I< 6CB46CET< W =D/ SEMM DW3, AH'?0%'4&FT z U<E6 S&, C m X<- W3, 6WT, U<-X S1, BWT, X<C] n
X<CF S:, 6WT, C<FX S8(1, 6WT< P7D) J0>%& 6]C<M uDsWvs ? m 6<XF :$% SD'?+0& AT<
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Journal of Medicinal Chemistry
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U<MB S8(1, -WT, X<U] S1, -WT, X<E] S1, -WT, X<BU S&&, C m E<M, B<M W3, -WT, X<6M S&, C F E<M W3, -WT,
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U<F] S1, -WT, X<]E S1, -WT, X<UC S1, -WT, X<F- S&, C m U<U W3, 6WT, F<UC S&, C m ]<M W3, 6WT, C<BB
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Page 25 of 40
Journal of Medicinal Chemistry
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Journal of Medicinal Chemistry
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X<B] S1, -WT, X<BE S&&, C m E<M, B<6 W3, -WT, X<-F S&, C m C<] W3, -WT, B<FB4B<BX S:, 6WT, -<-] S?, C
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-
:<I< -EU4-FMT< W =D/ SEMM DW3, 2D)`4&FT z -6<BB S1, -WT, ]<-U S1, -WT, X<XU S1, -WT, X<F-
S1, -WT, X<CC S1, -WT, X<BE S&&, C m E<M, B<B W3, -WT, X<-U S&, C m C<U W3, -WT, B<EU4B<B] S:, 6WT,
-<FC4-<EU S:, 6WT, -<BX S&&, C m -C<], X<C W3, 6WT, M<]B S?, C m X<C W3, BWT< P7D) J0>%& 6U]<MF
uDsWvs ? m -<]- :$% SD'?+0& AT<
, /
=:;<0>-&#>,%;D;"5@;=8;<=3=3=;0!-A5*&!&)*0"5@;BW;#*!-%,;:38;7-$(-%, <@,@. Sr$'"&o CXh,
-
8(0A% 10"$&, :<I< -CE4-CXT< W =D/ SEMM DW3, 2D)`4&FT z ]<-X S1, -WT, X<UM S1, -WT, X<E] S1,
6WT, X<BC S&&, C m E<M, B<B W3, -WT, X<-X S&, C m E<- W3, -WT, B<EU S&&, C m BC<-, -U<U W3, 6WT,
6<B]46<6X S:, 6WT, -<]M4-<UM S:, 6WT< P7D) J0>%& BCB<- uDsWvs ? m 6<-E :$% SD'?+0& AT<
, /
8;<=3=;7-A5*&!&#-#,!-7-%;?;"5@;=;<0>-&#>,%;D;"5@;BW;#*!-%;:;$(-%, <@7@. Sr$'"&o XBh,
-
"$*+? 8(0A% 10"$&, :<I< 6M]46--T< W =D/ SEMM DW3, 2D)`4&FT z -6<EX S1, -WT, ]<B- S1, -WT,
X<UU S1, -WT, X<E6 S1, -WT, X<BU S&&, C m E<-, B<6 W3, -WT, X<-X S&&, C m E<-, -<6 W3, -WT, C<EE n C<-X
S:, CWT, 6<-E n 6<MB S:, CWT< P7D) J0>%& BBX<-- uDsWvs ? m 6<FE :$% SD'?+0& AT<
, /
=;<0>-&#>,%;D;"5@;8;<=;<0!-A5*&!&(,0>"5@#-#,!-7-%;?;"5@;BW;#*!-%;:;$(-%, <@8@. Sr$'"&o
-
X6h, "$*+? K'""0A 10"$&, :<I< -B]4-C-T< W =D/ SEMM DW3, 2D)`4&FT z -6<EB S1, -WT, ]<6F S1,
-WT, X<UE S1, -WT, X<E6 S1, -WT, X<BU S&&, C m E<6, B<M W3, -WT, X<-X S&, C m E<6 W3, -WT, E<EE4E<CC
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Page 27 of 40
Journal of Medicinal Chemistry
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S:, -WT, B<MU S?, C m -6<B W3, 6WT, 6<XC46<XM S:, -WT, 6<-M4-<]C S:, BWT, -4E-4-<C6 S:, 6WT<
P7D) J0>%& BF]<-X uDsWvs ? m 6<XM :$% SD'?+0& AT<
, /
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-
:<I< -XB4-XET< W =D/ SEMM DW3, 2D)`4&FT z -6<BX S1, -WT, ]<6U S1, -WT, X<XU S1, -WT, X<F-
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S&, C m 6<] W3, -WT, X<BC S&&, C m E<-, B<B W3, -WT, X<-X S&&, C m E<-, M<X W3, -WT, C<E- n C<-- S:,
CWT, 6<CX n 6<BU S:, 6WT< P7D) J0>%& 6XB<MF uDsWvs ? m -<EX :$% SD'?+0& AT<
, /
=8;+"+5&>,6"5;=:;<0>-&#>,%;D;"5@;BW;#*!-%,;:38;7-$(-%, <@%@. Sr$'"&o XMh, 8(0A% 10"$&,
-
:<I< -XX4-X]T< W =D/ SEMM DW3, 2D)`4&FT z ]<-F S1, -WT, X<XU S1, -WT, X<E] S1, -WT, X<BE
S&&, C m C<], B<B W3, -WT, X<-U S&, C m C<E W3, 6WT, C<-C4C<MC S:, -WT, -<]]4-<]C S:, 6WT, -<UM n
-<XE S:, 6WT, -<FX4-<FC S:, -WT, -<B] n -<BM S:, BWT, -<6E4-<-F S:, 6WT< P7D) J0>%& B-E<-C
uDsWvs ? m 6<MU :$% SD'?+0& AT<
, /
=8;-'&#!&#"5;=:;<0>-&#>,%;D;"5@;BW;#*!-%,;:38;7-$(-%, <@&@. Sr$'"&o E]h, 8(0A% 10"$&,
-
:<I< -B64-BCT< W =D/ SEMM DW3, 2D)`4&FT z -6<BC S1, -WT, ]<-X S1, -WT, X<XU S1, -WT, X<F-
S1, -WT, X<BE S&&, C m E<M, B<B W3, -WT, X<-U S&, C m C<] W3, -WT, X<-C S&, C m F<F W3, -WT, B<-U S:,
-WT, -<6E S&, C m F<F W3, FWT< P7D) J0>%& 6XE<MU uDsWvs ? m -<U6 :$% SD'?+0& AT<
, /
=83=8;7-,0>"5;=:;<0>-&#>,%;D;"5@;BW;#*!-%,;:38;7-$(-%, <@#@. Sr$'"&o XXh, "$*+? 8(0A%
-
10"$&, :<I< UU4]MT< W =D/ SEMM DW3, 2D)`4&FT z -6<B] S1, -WT, ]<-C S1, -WT, X<UM S1, -WT,
X<EB S&, C m 6<E W3, -WT, X<BF S&&, C m E<-, B<6 W3, -WT, X<-U S&, C m E<- W3, -WT, B<]F S8(1, CWT,
-<66 S?, C m X<M W3, FWT< P7D) J0>%& 6U]<MF uDsWvs ? m -<U] :$% SD'?+0& AT<
, /
=8;+"+5&#!&#"5;=:;<0>-&#>,%;D;"5@;BW;#*!-%,;:38;7-$(-%, <@9@. Sr$'"&o XMh, "$*+? 8(0A%
-
10"$&, :<I< -BM4-B6T< W =D/ SEMM DW3, 2D)`4&FT z ]<66 S1, -WT, X<X] S1, -WT, X<XE S&, C m 6<-
W3, -WT, X<BC S&&, C m E<M, B<B W3, -WT, X<-] S&, C m E<M W3, -WT, -<6E4-<-E S:, 6WT, M<]M4M<FC S:,
BWT< P7D) J0>%& 6XB<- uDsWvs ? m -<-X :$% SD'?+0& AT<
, /
=8;<0,!0;)*0"5@;=:;<0>-&#>,%;D;"5@;BW;#*!-%,;:38;7-$(-%, <@!@. Sr$'"&o E]h, 8(0A% 10"$&,
-
:<I< -EM4-E6T< W =D/ SEMM DW3, 2D)`4&FT z ]<-C S1, -WT, X<XX S1, -WT, X<E] S1, -WT, X<BU n
X<B6 S:, -WT, X<6M S&, C m E<M W3, -WT, F<6E S1, -WT, -<EB S1, ]WT< P7D) J0>%& 6U]<6 uDsWvs ?
, /
m -<U6 :$% SD'?+0& AT<
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Journal of Medicinal Chemistry
Page 28 of 40
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=8;-'&)*0"5;=:;<0>-&#>,%;D;"5@;BW;#*!-%,;:38;7-$(-%, <@'@. Sr$'"&o 6-h, 0JJ4A+$?' 1':$4
-
10"$&T< W =D/ SEMM DW3, AH'?0%'4&FT z --<C6 S1, -WT, U<CF S1, -WT, X<XC S&, C m B<] W3, 6WT,
X<BB n X<6X S:, -WT, X<6B S&, C m C<U W3, -WT, F<FX S8(1, -WT, B<EM4B<CB S:, -WT, 6<UU S&, C m C<F
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W3, 6WT, M<]] S&, C m F<X W3, FWT< P7D) J0>%& 6U]<MF uDsWvs ? m -<UX :$% SD'?+0& AT<
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=8;+"+5&#,%0"5;=:;<0>-&#>,%;D;"5@;BW;#*!-%,;:38;7-$(-%, <@;@. Sr$'"&o UMh, "$*+? 8(0A%
-
10"$&, :<I< -6F4-6UT< W =D/ SEMM DW3, AH'?0%'4&FT z --<CM S1, -WT, U<CF S1, -WT, X<XC S1, 6WT,
X<6F S&, C m -U<- W3, 6WT, F<BX S&, C m E<U W3, -WT, C<EU S1, -WT, -<]] n -<CX S:, XWT< P7D) J0>%&
BM-<MU uDsWvs ? m -<]B :$% SD'?+0& AT<
, /
=8;<:;<#"!!&5-7-%;?;"5@,0>"5@;=:;<0>-&#>,%;D;"5@;BW;#*!-%,;:38;7-$(-%, <@*@.
Sr$'"&o
-
E-h, "$*+? 0(!%*' 10"$&, :<I< -F64-FCT< W =D/ SEMM DW3, 2D)`4&FT z -6<B6 S1, -WT, ]<-X S1,
-WT, X<XF S1, -WT, X<F- S1, -WT, X<B6 S&&, C m E<M, B<6 W3, -WT, X<-] S1, -WT, X<-F S?, C m E<M W3,
-WT, B<F] n B<C] S:, 6WT, B<-E S&, C m C<F W3, -WT, 6<FF S?, C m F<X W3, 6WT, -<X64-<F6 S:, CWT<
.?+('' !"$I+!?$H I(0?0%1 :'(*'& A$?+ 2D)` 1$*%!"< P7D) J0>%& BBM<- uDsWvs ?/ m -<-- :$%
,
SD'?+0& AT<
=:;<?;(,0>"5;?W;#"!$1&5;=;"5@;=8;<=3=3=;0!-A5*&!&)*0"5@;BW;#*!-%,;:38;7-$(-%,
<@$+@.
-
Sr$'"&o BXh, 0JJ4A+$?' 10"$&, :<I< 6XE46XXT< W =D/ SEMM DW3, 2D)`4&FT z ]<6U S1, -WT, U<EU
S8(1, -WT, U<6C S1, -WT, X<UC S1, -WT, X<E6 S1, -WT, B<UM S1, BWT, B<FE n B<E- S:, 6WT, 6<CE n 6<BX
S:, 6WT, -<]6 n -<U- S:, 6WT< P7D) J0>%& BC-<- uDsWvs ? m -<F- :$% SD'?+0& AT<
, /
=:;<?;(,0>"5;?W;#"!$1&5;=;"5@;=8;<:;<#"!!&5-7-%;?;"5@,0>"5@;BW;#*!-%,;:38;7-$(-%,
-
<@$2@. Sr$'"&o CUh, 8(0A% 10"$&, :<I< -6U4-BMT< W =D/ SEMM DW3, 2D)`4&FT z -6<6F S1, -WT,
U<E] S1, -WT, X<UX S1, -WT, X<X6 S1, -WT, X<CF S1, -WT, X<-E S1, -WT, B<XX S1, BWT, B<FX n B<EM S:,
BWT, 6<F] S?, C m F<U W3, 6WT, 6<EX 4 6<EB S:, BWT, -<XE n -<FX S:, CWT< P7D) J0>%& B6U<6B
uDsWvs ? m -<C] :$% SD'?+0& AT<
, /
=8;)*0"5;=:;<?;(,0>"5;?W;#"!$1&5;=;"5@;BW;#*!-%,;:38;7-$(-%, <@$,@. Sr$'"&o E-h, 0JJ4
-
A+$?' 10"$&, :<I< 6ME46MXT< W =D/ SCMM DW3, 72B`2T z X<U] S1, -WT, X<XB S1, -WT, X<EX S1,
-WT, B<UC S1, BWT, B<EX S&, C m X<6 W3, 6WT, -<FX S&&, C m -C<F, X<C W3, 6WT, -<CX S&&, C m -E<M, X<C
W3, 6WT, M<]] S?, C m X<C W3, BWT< P7D) J0>%& 6UX<- uDsWvs ? m -<CX :$% SD'?+0& AT<
, /
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Page 29 of 40
Journal of Medicinal Chemistry
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8;(&!#>&5-%&;=;<0>-&#>,%;D;"5@;BW;#*!-%;:;$(-%, <@3@. Sr$'"&o E6h, "$*+? K'""0A 10"$&,
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S1, -WT, X<BX S&&, C m C<], B<B W3, -WT, X<-F S&, C m E<M W3, -WT, C<BM4C<-M S:, CWT, B<XF4B<XM S:,
CWT< P7D) J0>%& BMB<M uDsWvs ? m -<U] :$% SD'?+0& AT<
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8;<=;(,0>"5#-#,!$1-%;?;"5@;=;<0>-&#>,%;D;"5@;BW;#*!-%;:;$(-%, <@4@. Sr$'"&o F-h, "$*+?
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S1, -WT, X<E- S&, C m 6<C W3, -WT, X<BX S&&, C m E<-, B<6 W3, -WT, X<-F S&&, C m E<M, -<M W3, -WT,
C<B64C<MU S:, CWT, 6<CE46<C- S:, CWT, 6<6B S1, BWT< P7D) J0>%& B-F<- uDsWvs ?/ m -<6U :$%
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SD'?+0& AT<
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-
:<I< -UM4-U6T< W =D/ SEMM DW3, 2D)`4&FT z -6<CC S1, -WT, ]<-X S1, -WT, X<UM S1, -WT, X<E-
S&, C m 6<C W3, -WT, X<BF S&&, C m E<-, B<6 W3, -WT, X<-X S&&, C m E<-, -<6 W3, -WT, C<6B4C<MU S:,
CWT, B<-U S&, C m C<U W3, 6WT, -<F]4-<E] S:, CWT< P7D) J0>%& BM-<M uDsWvs ?/ m 6<-] :$%
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SD'?+0& AT<
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10"$&, :<I< 6MU46-MT< W =D/ SEMM DW3, 2D)`4&FT z -6<BE S1, -WT, ]<-X S1, -WT, X<XX S1, -WT,
X<FM S&&, C m B<6, -<6 W3, -WT, X<BE S&&, C m E<-, B<B W3, -WT, X<-U S&&, C m E<-, -<6 W3, -WT, C<--4
C<MC S&&, C m 6U<6, U<C W3, BWT, B<-U S&, C m E<B W3, -WT, 6<M6 n -<]B S:, CWT< P7D) J0>%& 6UX<M
uDsWvs ? m -<XE :$% SD'?+0& AT<
, /
ACS Paragon Plus Environment
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