Synthesis and biological evaluation of the LINS01 series as procognitive agents: a multitarget approach

• Grant number: 16/23139-2
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: April 01, 2017
• End date: May 31, 2021
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: João Paulo dos Santos Fernandes
• Grantee: Michelle Fidelis Corrêa
• Host Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil

Abstract

Most neurological disorders are associated with some cognitive decline. The mechanisms governing memory and learning processes are complex and commonly explored in the search for targets to pharmacological therapy. Certain pathological conditions, such as Alzheimer's and Parkinson's disease, vascular dementia and mood disorders affect cognition. Therefore, the search for new molecules capable of improving the cognitive processes is something common in pharmaceutical companies as well as in academic research. It is proposed that such diseases are best addressed through the multitarget approach, i.e. by acting in more than one target simultaneously. The role of the histaminergic, cholinergic, and dopaminergic systems, along with the inflammatory process, is widely known, and so these systems can be considered promising to reach new drugs. In this respect, this project aims to synthesize and evaluate the activity of compounds from LINS01 series (dihydrobenzofuranyl-piperazines and dihydroindole-piperazines) in pharmacological tests in vitro (affinity and functional activity) on H3R, H4R, D2R, D3R and AChE. The compounds will be prepared by methodologies developed by the group, involving the phenols/anilines as starting material for reactions of allylation, thermal rearrangement, cyclization and alkylation. It is expected that the designed series will bring information about SAR, important for optimizing the activity of new compounds in each target, as well as in the multitarget strategy. (AU)

Scientific publications

(10)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

GINOZA, MILTON; FERNANDES, GUSTAVO A. B.; CORREA, MICHELLE F.; FERNANDES, JOAO PAULO S.. Novel potent vasodilating agents: Evaluation of the activity and potency of LINS01005 and derivatives in rat aorta. European Journal of Pharmaceutical Sciences, v. 143, FEB 15 2020. (17/05441-6, 16/23139-2, 16/25028-3)

FRANCHIN, TAISA BUSARANHO; ULIAN SILVA, BRUNA CRISTINA; DEGRANDIS, RONE APARECIDO; CORREA, MICHELLE FIDELIS; SIMOES DE QUEIROZ ARANHA, CECILIA MARIA; FERNANDES, JOAO PAULO S.; CAMPOS, MICHEL LEANDRO; PECCININI, ROSANGELA GONCALVES. Assessment of the Physicochemical Properties and Stability for Pharmacokinetic Prediction of Pyrazinoic Acid Derivatives. CURRENT DRUG METABOLISM, v. 21, n. 9, p. 714-721, 2020. (16/23139-2, 16/25028-3, 16/23229-1)

SOLIANI, ANDRESSA; KUBOTA, SILVIA MEGUMI; CORREA, MICHELLE FIDELIS; CERUTTI, SUZETE MARIA; FERNANDES, JOAO PAULO S.. Differential contribution of H3R antagonism by LINS01 compounds on memory, anxiety-like behaviour and spontaneous locomotor activity in healthy rats. Behavioural Brain Research, v. 377, JAN 13 2020. (16/18039-9, 16/25028-3, 16/23139-2)

CORREA, MICHELLE F.; BARBOSA, ALEFE J. R.; TEIXEIRA, LARISSA B.; DUARTE, DIEGO A.; SIMOES, SARAH C.; PARREIRAS-E-SILVA, LUCAS T.; BALBINO, ALEKSANDRO M.; LANDGRAF, RICHARDT G.; BOUVIER, MICHEL; COSTA-NETO, CLAUDIO M.; et al. Pharmacological Characterization of 5-Substituted 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazines: Novel Antagonists for the Histamine H-3 and H-4 Receptors with Anti-inflammatory Potential. FRONTIERS IN PHARMACOLOGY, v. 8, NOV 14 2017. (12/20148-0, 17/02042-3, 16/23139-2, 16/25028-3, 13/20479-9)

CORRE, MICHELLE F.; BALICO-SILVA, ANDRE L.; KISS, DORA J.; FERNANDES, GUSTAVO A. B.; MARASCHIN, JHONATAN C.; PARREIRAS-E-SILVA, LUCAS T.; VARELA, MARINA T.; SIMOES, SARAH C.; BOUVIER, MICHEL; KESERU, GYORGY M.; et al. Novel potent (dihydro)benzofuranyl piperazines as human histamine receptor ligands - Functional characterization and modeling studies on H-3 and H(4 )receptors. Bioorganic & Medicinal Chemistry, v. 30, JAN 15 2021. (16/24120-3, 17/05441-6, 12/20148-0, 16/25028-3, 18/03918-2, 18/00153-5, 16/08920-0, 16/23139-2)

LOPES, FLAVIA B.; ARANHA, CECILIA M. S. Q.; CORREA, MICHELLE F.; FERNANDES, GUSTAVO A. B.; OKAMOTO, DEBORA N.; SIMOES, LEONARDO P. M.; JUNIOR, NAILTON M. N.; FERNANDES, JOAO PAULO S.. Evaluation of the histamine H-3 receptor antagonists from LINS01 series as cholinesterases inhibitors: Enzymatic and modeling studies. CHEMICAL BIOLOGY & DRUG DESIGN, v. 100, n. 5, p. 8-pg., 2022-09-08. (21/03387-0, 19/24028-8, 16/23139-2)

DOS SANTOS, LAISA ALIANDRO; DOS SANTOS, GABRIELA SALLES; BORGES FERNANDES, GUSTAVO ARIEL; CORREA, MICHELLE FIDELIS; DE FARIA ALMEIDA, CAROLINA APARECIDA; FERNANDES, LILIAM; MARCOURAKIS, TANIA; FERNANDES, JOAO PAULO S.; TAMBORELLI GARCIA, RAPHAEL CAIO. Neurotoxicity Assessment of 1-[(2,3-Dihydro-1-Benzofuran-2-yl)Methyl]Piperazine (LINS01 Series) Derivatives and their Protective Effect on Cocaine-Induced Neurotoxicity Model in SH-SY5Y Cell Culture. NEUROTOXICITY RESEARCH, v. 40, n. 6, p. 11-pg., 2022-11-07. (17/21834-8, 16/23139-2)

CORREA, MICHELLE FIDELIS; RAMOS BARBOSA, ALEFE JHONATAS; BORGES FERNANDES, GUSTAVO ARIEL; BAKER, JILLIAN G.; DOS SANTOS FERNANDES, JOAO PAULO. Pharmacological and SAR analysis of the LINS01 compounds at the human histamine H-1, H-2, and H-3 receptors. CHEMICAL BIOLOGY & DRUG DESIGN, v. 93, n. 1, p. 89-95, JAN 2019. (16/25028-3, 17/05441-6, 16/23139-2)

BALBINO, A. M.; LIMA, L. J. S.; FERNANDES, G. A. B.; CORREA, M. F.; LANDGRAF, M. A. V.; FERNANDES, J. P. S.; LANDGRAF, R. G.. MODULATORY EFFECTS OF HISTAMINE H3R/H4R ANTAGONISTS LINS01005 AND LINS01007 ON THE INFLAMMATORY RESPONSE IN MURINE ASTHMA MODEL. Inflammation Research, v. 68, p. 1-pg., 2019-07-01. (12/51104-8, 17/02042-3, 16/23139-2, 16/25028-3, 17/05441-6)

CORREA, M. F.; SILVA, A. B.; PENOMIAN, L.; SIMOES, S. C.; FERNANDES, G. A. B.; ARANHA, C. M. S. Q.; VARELA, M. T.; COSTA-NETO, C. M.; FERNANDES, J. P. S.. EVALUATION AND SAR STUDY OF NOVEL SUBSTITUTED (DIHYDRO)BENZOFURANYL-PIPERAZINES AS HISTAMINE H3R AND H4R LIGANDS. Inflammation Research, v. 68, p. 1-pg., 2019-07-01. (18/04488-1, 18/03918-2, 16/23139-2, 16/25028-3, 17/05441-6)