Substituted aryl-alkylamide-piperazines as multitarget ligands: synthesis and assessment of the activity on relevant targets for the treatment of CNS disorders

• Grant number: 19/24028-8
• Support Opportunities: Regular Research Grants
• Start date: June 01, 2021
• End date: January 31, 2024
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: João Paulo dos Santos Fernandes
• Grantee: João Paulo dos Santos Fernandes
• Host Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil
• Associated researchers: Marcelo Tadeu Marin ; Suzete Maria Cerutti
• Associated research grant(s): 24/02208-2 - 51st Annual Meeting of the European Histamine Research Society (EHRS) and 1st Annual Meeting of the Histamine Research Society of Europe (HRSE), AR.EXT

Abstract

The cerebral mechanism related to the control of several neurological disorders (especially Alzheimer's and Parkinson's diseases, affective and mood disorders) are complex and diverse. This heterogeneous nature suggests that the multitarget approach can be the most appropriate in the treatment of such conditions, since it can interfere with more than one target simultaneously and provide net therapeutic gain. The role of the histaminergic, dopaminergic and cholinergic systems are well established on the development of these disfunctions, and can be considered among the main targets to new drugs. In this scenario, this project aims to prepare and evaluate a set of anilidoalkyl-piperazines with changes on the terminal nitrogen of the piperazine and in the aniline. The compounds will be prepared through classical methods already performed in the working group, that usually lead to good yields, and will be tested as ligands of the histamine H3 and dopamine D3 receptors and acetylcholinesterase on in vitro protocols. The functional activity on these targets and the selectivity against H4, D2 e butirylcholinesterase will also be assessed, as well as the vasodilating activity. It is expected that the results from this proposal may identify novel promising compounds, and these information will be added to other data obtained in the group to optimize the activity on each target and afterwards obtain molecules that interact with all three targets. In vivo assays on discriminative memory model will be performed to the best compounds indeed. (AU)

Scientific publications

(6)

(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)

VARELA, MARINA T.; AMARAL, MAIARA; ROMANELLI, MAIARA M.; LEVATTI, ERICA V. DE CASTRO; TEMPONE, ANDRE G.; FERNANDES, JOAO PAULO S.. Optimization of physicochemical properties is a strategy to improve drug-likeness associated with activity: Novel active and selective compounds against Trypanosoma cruzi. European Journal of Pharmaceutical Sciences, v. 171, p. 12-pg., 2022-04-01. (21/04464-8, 19/14167-0, 18/03918-2, 20/03637-3, 19/24028-8)

WALLER, STEFANIE BRESSAN; CLEFF, MARLETE BRUM; RIPOLL, MARCIA KUTSCHER; ARAUJO MEIRELES, MARIO CARLOS; FERRARINI, MARCIO; VARELA, MARINA THEMOTEO; FERNANDES, JOAO PAULO S.. ioisosteric modification on benzylidene-carbonyl compounds improved the drug-likeness and maintained the antifungal activity against Sporothrix brasiliensi. CHEMICAL BIOLOGY & DRUG DESIGN, v. 99, n. 3, DEC 2021. (18/03918-2, 19/24028-8, 16/25028-3)

VARELA, MARINA T.; ROMANELLI, MAIARA; AMARAL, MAIARA; TEMPONE, ANDRE G.; FERNANDES, JOAO PAULO S.. Piperazine amides with desirable solubility, physicochemical and drug-like properties: Synthesis and evaluation of the anti-Trypanosoma cruzi activity. SAUDI PHARMACEUTICAL JOURNAL, v. 31, n. 7, p. 9-pg., 2023-06-01. (21/04464-8, 19/24028-8, 19/14167-0, 18/03918-2)

AMARAL, MAIARA; VARELA, MARINA T.; KANT, RAVI; CHRISTODOULIDES, MYRON; FERNANDES, JOAO PAULO S.; TEMPONE, ANDRE G.. Synthetic Analogues of Gibbilimbol B Induce Bioenergetic Damage and Calcium Imbalance in Trypanosoma cruzi. LIFE-BASEL, v. 13, n. 3, p. 17-pg., 2023-03-01. (21/04464-8, 18/26655-7, 17/50333-7, 18/03918-2, 19/24028-8, 18/25128-3)

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)

ARANHA, CECILIA M. S. Q.; REINER-LINK, DAVID; LEITZBACH, LUISA R.; LOPES, FLAVIA B.; STARK, HOLGER; FERNANDES, JOAO PAULO S.. Multitargeting approaches to cognitive impairment: Synthesis of aryl-alkylpiperazines and assessment at cholinesterases, histamine H3 and dopamine D3 receptors. Bioorganic & Medicinal Chemistry, v. 78, p. 10-pg., 2022-12-19. (19/24028-8, 21/03387-0)