Towards Arginase Inhibition: Hybrid SAR Protocol for Property
Mapping of Chlorinated N-arylcinnamamides

J 2023

Towards Arginase Inhibition: Hybrid SAR Protocol for Property Mapping of Chlorinated N-arylcinnamamides

BAK, Andrzej; Jiří KOS; Gilles DEGOTTE; Aleksandra SWIETLICKA; Tomáš STRHÁRSKY et. al.

Basic information

Original name

Towards Arginase Inhibition: Hybrid SAR Protocol for Property Mapping of Chlorinated N-arylcinnamamides

Authors

BAK, Andrzej (616 Poland); Jiří KOS (203 Czech Republic, belonging to the institution); Gilles DEGOTTE (112 Belarus); Aleksandra SWIETLICKA (616 Poland); Tomáš STRHÁRSKY (703 Slovakia, belonging to the institution); Dominika PINDJAKOVA (703 Slovakia); Tomáš GONĚC (203 Czech Republic, belonging to the institution); Adam SMOLINSKI (616 Poland); Pierre FRANCOTTE (56 Belgium); Michel FREDERICH (56 Belgium); Violetta KOZIK (616 Poland) and Josef JAMPÍLEK (203 Czech Republic, guarantor)

Edition

International Journal of Molecular Sciences, BASEL, MDPI, 2023, 1661-6596

Other information

Language

English

Type of outcome

Article in a journal

Field of Study

30104 Pharmacology and pharmacy

Country of publisher

Switzerland

Confidentiality degree

is not subject to a state or trade secret

References:

URL

Impact factor

Impact factor: 4.900

RIV identification code

RIV/00216224:14110/23:00132378

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.3390/ijms24043611

UT WoS

000945149600001

EID Scopus

2-s2.0-85149012776

Keywords in English

arginase inhibition; arylcinnamamides; lipophilicity; CoMSA; molecular docking; similarity-activity landscape index

Abstract

In the original language

A series of seventeen 4-chlorocinnamanilides and seventeen 3,4-dichlorocinnamanilides were characterized for their antiplasmodial activity. In vitro screening on a chloroquine-sensitive strain of Plasmodium falciparum 3D7/MRA-102 highlighted that 23 compounds possessed IC50 < 30 mu M. Typically, 3,4-dichlorocinnamanilides showed a broader range of activity compared to 4-chlorocinnamanilides. (2E)-N-[3,5-bis(trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-en-amide with IC50 = 1.6 mu M was the most effective agent, while the other eight most active derivatives showed IC50 in the range from 1.8 to 4.6 mu M. A good correlation between the experimental logk and the estimated clogP was recorded for the whole ensemble of the lipophilicity generators. Moreover, the SAR-mediated similarity assessment of the novel (di)chlorinated N-arylcinnamamides was conducted using the collaborative (hybrid) ligand-based and structure-related protocols. In consequence, an 'averaged' selection-driven interaction pattern was produced based in namely 'pseudo-consensus' 3D pharmacophore mapping. The molecular docking approach was engaged for the most potent antiplasmodial agents in order to gain an insight into the arginase-inhibitor binding mode. The docking study revealed that (di)chlorinated aromatic (C-phenyl) rings are oriented towards the binuclear manganese cluster in the energetically favorable poses of the chloroquine and the most potent arginase inhibitors. Additionally, the water-mediated hydrogen bonds were formed via carbonyl function present in the new N-arylcinnamamides and the fluorine substituent (alone or in trifluoromethyl group) of N-phenyl ring seems to play a key role in forming the halogen bonds.

Cite

BAK, Andrzej; Jiří KOS; Gilles DEGOTTE; Aleksandra SWIETLICKA; Tomáš STRHÁRSKY; Dominika PINDJAKOVA; Tomáš GONĚC; Adam SMOLINSKI; Pierre FRANCOTTE; Michel FREDERICH; Violetta KOZIK and Josef JAMPÍLEK. Towards Arginase Inhibition: Hybrid SAR Protocol for Property Mapping of Chlorinated N-arylcinnamamides. International Journal of Molecular Sciences. BASEL: MDPI, 2023, vol. 24, No 4, p. 1-23. ISSN 1661-6596. Available from: https://dx.doi.org/10.3390/ijms24043611.

@article{2344439,
   author = {Bak, Andrzej and Kos, Jiří and Degotte, Gilles and Swietlicka, Aleksandra and Strhársky, Tomáš and Pindjakova, Dominika and Goněc, Tomáš and Smolinski, Adam and Francotte, Pierre and Frederich, Michel and Kozik, Violetta and Jampílek, Josef},
   article_location = {BASEL},
   article_number = {4},
   doi = {http://dx.doi.org/10.3390/ijms24043611},
   keywords = {arginase inhibition; arylcinnamamides; lipophilicity; CoMSA; molecular docking; similarity-activity landscape index},
   language = {eng},
   issn = {1661-6596},
   journal = {International Journal of Molecular Sciences},
   title = {Towards Arginase Inhibition: Hybrid SAR Protocol for Property Mapping of Chlorinated N-arylcinnamamides},
   url = {https://www.mdpi.com/1422-0067/24/4/3611},
   volume = {24},
   year = {2023}
}

TY  - JOUR
ID  - 2344439
AU  - Bak, Andrzej - Kos, Jiří - Degotte, Gilles - Swietlicka, Aleksandra - Strhársky, Tomáš - Pindjakova, Dominika - Goněc, Tomáš - Smolinski, Adam - Francotte, Pierre - Frederich, Michel - Kozik, Violetta - Jampílek, Josef
PY  - 2023
TI  - Towards Arginase Inhibition: Hybrid SAR Protocol for Property Mapping of Chlorinated N-arylcinnamamides
JF  - International Journal of Molecular Sciences
VL  - 24
IS  - 4
SP  - 1-23
EP  - 1-23
PB  - MDPI
SN  - 16616596
KW  - arginase inhibition
KW  - arylcinnamamides
KW  - lipophilicity
KW  - CoMSA
KW  - molecular docking
KW  - similarity-activity landscape index
UR  - https://www.mdpi.com/1422-0067/24/4/3611
N2  - A series of seventeen 4-chlorocinnamanilides and seventeen 3,4-dichlorocinnamanilides were characterized for their antiplasmodial activity. In vitro screening on a chloroquine-sensitive strain of Plasmodium falciparum 3D7/MRA-102 highlighted that 23 compounds possessed IC50 < 30 mu M. Typically, 3,4-dichlorocinnamanilides showed a broader range of activity compared to 4-chlorocinnamanilides. (2E)-N-[3,5-bis(trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-en-amide with IC50 = 1.6 mu M was the most effective agent, while the other eight most active derivatives showed IC50 in the range from 1.8 to 4.6 mu M. A good correlation between the experimental logk and the estimated clogP was recorded for the whole ensemble of the lipophilicity generators. Moreover, the SAR-mediated similarity assessment of the novel (di)chlorinated N-arylcinnamamides was conducted using the collaborative (hybrid) ligand-based and structure-related protocols. In consequence, an 'averaged' selection-driven interaction pattern was produced based in namely 'pseudo-consensus' 3D pharmacophore mapping. The molecular docking approach was engaged for the most potent antiplasmodial agents in order to gain an insight into the arginase-inhibitor binding mode. The docking study revealed that (di)chlorinated aromatic (C-phenyl) rings are oriented towards the binuclear manganese cluster in the energetically favorable poses of the chloroquine and the most potent arginase inhibitors. Additionally, the water-mediated hydrogen bonds were formed via carbonyl function present in the new N-arylcinnamamides and the fluorine substituent (alone or in trifluoromethyl group) of N-phenyl ring seems to play a key role in forming the halogen bonds.
ER  -

BAK, Andrzej; Jiří KOS; Gilles DEGOTTE; Aleksandra SWIETLICKA; Tomáš STRHÁRSKY; Dominika PINDJAKOVA; Tomáš GONĚC; Adam SMOLINSKI; Pierre FRANCOTTE; Michel FREDERICH; Violetta KOZIK and Josef JAMPÍLEK. Towards Arginase Inhibition: Hybrid SAR Protocol for Property Mapping of Chlorinated N-arylcinnamamides. \textit{International Journal of Molecular Sciences}. BASEL: MDPI, 2023, vol.~24, No~4, p.~1-23. ISSN~1661-6596. Available from: https://dx.doi.org/10.3390/ijms24043611.

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