1. Acilguanidinas e guanidinas an?logas de alcaloides bromopirr?licos, planejadas como inibidores seletivos de butirilcolinesterase
- Author
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Goulart, Paula do Nascimento, Lacerda, Renata Barbosa, K?mmerle, Arthur Eugen, Alves, Marina Amaral, Romeiro, Nelilma Correia, Tinoco, Luzineide Wanderley, and Salles, Cristiane Martins Cardoso de
- Subjects
Qu?mica ,qu?mica medicinal ,medicinal chemistry ,marine alkaloids ,acilguanidinas ,guanidinas ,Butirilcolinesterase ,acylguanidines ,alcaloides marinhos ,guanidines - Abstract
Submitted by Jorge Silva (jorgelmsilva@ufrrj.br) on 2022-05-27T20:18:54Z No. of bitstreams: 1 2021 - Paula do Nascimento Goulart.pdf: 12696775 bytes, checksum: e4efcc1c63466d6b6664c6d3318549e9 (MD5) Made available in DSpace on 2022-05-27T20:18:54Z (GMT). No. of bitstreams: 1 2021 - Paula do Nascimento Goulart.pdf: 12696775 bytes, checksum: e4efcc1c63466d6b6664c6d3318549e9 (MD5) Previous issue date: 2021-04-29 CAPES - Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior 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 (N-Boc) 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'-bis-protected 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 22.8?M) and BuChE (CI50 of 27.3 ?M) and 50c as a selective inhibitor of BuChE (IC50 of 13.3 ?M). Acylguanidines stood out as selective BuChE inhibitors, mainly free acylguanidines 51a and 51g with IC50 of 4.8 ?M and 3.8 ?M, respectively, and 52c, 52d and 52f with BuChE inhibition greater than 83% at 30 ?M. 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. Os produtos naturais s?o uma das principais fontes de inspira??o para o desenvolvimento de novos candidatos a prot?tipos de f?rmacos. Dentre os produtos de origem natural, os alcaloides bromopirr?licos s?o de grande interesse dos qu?micos medicinais por serem uma classe de metab?litos secund?rios exclusivamente marinhos, produzidos por esponjas, e com diversas atividades biol?gicas. O presente trabalho descreve o planejamento estrutural, a s?ntese e avalia??o, in vitro e in silico, de novos derivados bromopirr?licos guanid?nicos e acilguanid?nicos desenhados como an?logos estruturais de alcaloides marinhos oroid?nicos. O planejamento estrutural se baseou em estrat?gias como o bioisosterismo, hibrida??o molecular e homologa??o para o planejamento de modifica??es nas subunidades caracter?sticas destes alcaloides, como a cadeia alqu?lica espa?adora e a subunidade guanid?nica c?clica. A estrat?gia sint?tica explorou a rea??o de condensa??o entre o intermedi?rio-chave 1-(terc-butiloxicarbonil)-3-(4,5-dibromopirrol-2-carbonil)-2-metil-2-isotioureia com diferentes aminas e posterior remo??o do grupo de prote??o (N-Boc) em meio ?cido para a obten??o das acilguanidinas alvo. Os an?logos guanid?nicos ac?clicos foram obtidos atrav?s da rea??o entre o intermedi?rio 2-tricloroacetil-4,5-dibromopirrol, ou 2-tricloroacetil-pirrol, e amino-alquilguanidinas N,N?-bis-protegidas previamente sintetizadas, e posterior rea??o de desprote??o em meio ?cido. Foram sintetizados em bons rendimentos 32 compostos originais (68a-c; 69a-c; 50a-f; 62a-h; 62g?; 62h?; 51a-h; 51g?; 51h?), entre guanidinas e acilguanidinas (protegidas e desprotegidas), an?logos sint?ticos dos alcaloides marinhos oroid?nicos, todos caracterizados por RMN de 1H e RMN de 13C. A triagem in vitro sobre as enzimas acetilcolinesterase (AChE) e butirilcolinesterase (BuChE) identificou a guanidina 68c como um inibidor n?o seletivo de AChE (CI50 de 22,8?M) e BuChE (CI50 de 27,3 ?M) e 50c como um inibidor seletivo de BuChE (CI50 de 13,3?M). As acilguanidinas se destacaram como inibidores seletivos de BuChE, principalmente as acilguanidinas livres 51a e 51g com CI50 de 4,8 ?M e 3,8 ?M, respectivamente, e 52c, 52d e 52f com inibi??o da BuChE maior que 83% a 30 ?M. A rela??o estrutura-atividade mostrou a import?ncia da fun??o acilguanidina livre para a inibi??o seletiva de BuChE, assim como a presen?a dos substituintes bromos no anel. Os estudos de docking molecular corroboraram os resultados experimentais mostrando a import?ncia das subunidades bromopirrol, acilguanidina e anel benz?lico para intera??o com os res?duos de amino?cidos presentes no s?tio ativo da BuChE. Adicionalmente, a avalia??o in silico das propriedades ADME e druglike mostrou que as novas guanidinas e acilguanidinas bromopirr?licas tem potencial para boa absor??o gastrointestinal e bom perfil drug-likeness.
- Published
- 2021