PPGQ
PROGRAMA DE PÓS-GRADUAÇÃO EM QUÍMICA
INSTITUTO DE QUÍMICA
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http://cursos.ufrrj.br/posgraduacao/ppgq
Banca de DEFESA: PAULA DO NASCIMENTO GOULART
Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.STUDENT : PAULA DO NASCIMENTO GOULART
DATE: 29/04/2021
TIME: 13:00
LOCAL: Remoto
TITLE:
Acylguanidines and guanidines analogous to bromopyrrolic alkaloids, designed as selective butyrylcholinesterase inhibitors
KEY WORDS:
acylguanidines, guanidines, marine alkaloids, medicinal chemistry.
PAGES: 230
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUBÁREA: Química Orgânica
SPECIALTY: Síntese Orgânica
SUMMARY:
Natural products are one of the main sources of inspiration for development of new drug
prototypes candidates. Among products of natural origin, bromopyrrolic alkaloids are of
great interest to medicinal chemists because they are a class of exclusively marine
secondary metabolites, produced by sponges, and with diverse biological activities. The
present work describes design, synthesis and evaluation, in vitro and in silico, of new
guanidines and acylguanidines bromopyrrole derivatives designed as structural analogues
of oroidine marine alkaloids. Structural planning was based on strategies such as
bioisosterism, molecular hybridization and homologation for planning changes in the
characteristic subunits of these alkaloids, such as the spacer alkyl chain and the cyclic
guanidine subunit. Synthetic strategy explored the condensation reaction between the key
intermediate 1-(tert-butyloxycarbonyl)-3-(4,5-dibromopyrrol-2-carbonyl)-2-methyl-2-
isothiourea with different amines and subsequent removal of the protection group (NBoc) in acid medium to obtain the target acylguanidines. The acyclic guanidinic analogs
were obtained by the reaction between the intermediate 2-trichloroacetyl-4,5-
dibromopyrrole, or 2-trichloroacetyl-pyrrole, and previously synthesized N,N'-bisprotected amino-alkylguanidines, and subsequent deprotection reaction in acidic medium.
We synthesized 32 original compounds (68a-c; 69a-c; 50a-f; 62a-h; 62g'; 62h'; 51a-h;
51g'; 51h') in good yields, among guanidines and acylguanidines (protected and
unprotected), which are synthetic analogs of oroidinic marine alkaloids, all characterized
by 1H NMR and 13C NMR. In vitro screening for acetylcholinesterase (AChE) and
butyrylcholinesterase (BuChE) inhibition, identified guanidine 68c as a non-selective
inhibitor of AChE (CI50 of 22.8µM) and BuChE (CI50 of 27.3 µM) and 50c as a selective
inhibitor of BuChE (IC50 of 13.3 µM). Acylguanidines stood out as selective BuChE
inhibitors, mainly free acylguanidines 51a and 51g with IC50 of 4.8 µM and 3.8 µM,
respectively, and 52c, 52d and 52f with BuChE inhibition greater than 83% at 30 µM.
Structure-activity relationship showed the importance of free acylguanidine function for
selective inhibition of BuChE, as well as the presence of bromine substituents in pyrrole
ring. The molecular docking studies corroborated by showing the importance of
bromopyrrole, acylguanidine and benzyl ring subunits for interaction with the amino acid
residues in BuChE active site. Additionally, in silico evaluation of ADME and druglike
properties showed that new bromopyrrole guanidines and acylguanidines have the
potential for good gastrointestinal absorption and good drug-likeness properties.
prototypes candidates. Among products of natural origin, bromopyrrolic alkaloids are of
great interest to medicinal chemists because they are a class of exclusively marine
secondary metabolites, produced by sponges, and with diverse biological activities. The
present work describes design, synthesis and evaluation, in vitro and in silico, of new
guanidines and acylguanidines bromopyrrole derivatives designed as structural analogues
of oroidine marine alkaloids. Structural planning was based on strategies such as
bioisosterism, molecular hybridization and homologation for planning changes in the
characteristic subunits of these alkaloids, such as the spacer alkyl chain and the cyclic
guanidine subunit. Synthetic strategy explored the condensation reaction between the key
intermediate 1-(tert-butyloxycarbonyl)-3-(4,5-dibromopyrrol-2-carbonyl)-2-methyl-2-
isothiourea with different amines and subsequent removal of the protection group (NBoc) in acid medium to obtain the target acylguanidines. The acyclic guanidinic analogs
were obtained by the reaction between the intermediate 2-trichloroacetyl-4,5-
dibromopyrrole, or 2-trichloroacetyl-pyrrole, and previously synthesized N,N'-bisprotected amino-alkylguanidines, and subsequent deprotection reaction in acidic medium.
We synthesized 32 original compounds (68a-c; 69a-c; 50a-f; 62a-h; 62g'; 62h'; 51a-h;
51g'; 51h') in good yields, among guanidines and acylguanidines (protected and
unprotected), which are synthetic analogs of oroidinic marine alkaloids, all characterized
by 1H NMR and 13C NMR. In vitro screening for acetylcholinesterase (AChE) and
butyrylcholinesterase (BuChE) inhibition, identified guanidine 68c as a non-selective
inhibitor of AChE (CI50 of 22.8µM) and BuChE (CI50 of 27.3 µM) and 50c as a selective
inhibitor of BuChE (IC50 of 13.3 µM). Acylguanidines stood out as selective BuChE
inhibitors, mainly free acylguanidines 51a and 51g with IC50 of 4.8 µM and 3.8 µM,
respectively, and 52c, 52d and 52f with BuChE inhibition greater than 83% at 30 µM.
Structure-activity relationship showed the importance of free acylguanidine function for
selective inhibition of BuChE, as well as the presence of bromine substituents in pyrrole
ring. The molecular docking studies corroborated by showing the importance of
bromopyrrole, acylguanidine and benzyl ring subunits for interaction with the amino acid
residues in BuChE active site. Additionally, in silico evaluation of ADME and druglike
properties showed that new bromopyrrole guanidines and acylguanidines have the
potential for good gastrointestinal absorption and good drug-likeness properties.
BANKING MEMBERS:
Presidente - 1979542 - RENATA BARBOSA LACERDA
Interno - 1735975 - CEDRIC STEPHAN GRAEBIN
Interna - 1681790 - CRISTIANE MARTINS CARDOSO DE SALLES
Externa à Instituição - NELILMA CORREIA ROMEIRO - UFRJ
Externa à Instituição - MARIA LETÍCIA DE CASTRO BARBOSA - UFRJ
Externa à Instituição - MARINA AMARAL ALVES - UFRJ
Externa à Instituição - LUZINEIDE WANDERLEY TINOCO - UFRJ
Notícia cadastrada em: 23/04/2021 07:07
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