Strategies for the Synthesis of Structurally Complex Heterocycles and Evaluation of Potential Biological Activities

• Grant number: 23/18007-3
• Support Opportunities: Regular Research Grants
• Start date: April 01, 2024
• End date: March 31, 2026
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Fernando Antonio Santos Coelho
• Grantee: Fernando Antonio Santos Coelho
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated researchers: Fábio de Souza Fernandes ; Lucas Andre Zeoly

Abstract

This research project aims to explore the potential of the Morita-Baylis-Hillman reaction as a strategy for accessing poly-functionalized molecules with potential commercial applications. It is divided into four subprojects, all focused on the design and synthesis of heterocyclic compounds with significant structural diversity, incorporating fragments that hold potential for activity in both medicinal chemistry and the field of new materials. The chemistry explored in this research project holds great relevance for strategic sectors of the country, such as the pharmaceutical and new materials sectors. Specifically for the pharmaceutical sector, it is noteworthy that nitrogen-containing heterocycles represent over 85% of the total drugs marketed in Brazil and worldwide.In the first subproject, we will explore the developments of a recently published work concerning the synthesis of polycyclic indolizines. In this subproject, we intend to access new heterocycles that combine the frameworks of an indolizine and a naphthiridine into a single structure. The biological profile of these new complex heterocycles will be evaluated against human cancer cell lines. The photo-physical profile of these new heterocycles will also be assessed.In the second subproject, we will explore aromatic diketones (acenaphthoquinone and phenanthrene-9,10-quinone) as substrates for a Morita-Baylis-Hillman reaction, aiming to obtain complex pyrrolic systems. The behavior of these complex pyrrolic systems as substrates in acid-catalyzed reactions will also be evaluated. The objective is to obtain even more complex heterocycles through intramolecular cyclization reactions.In the third subproject, we plan to utilize computational chemistry tools and mechanistic studies to identify vinyl-heterocycles that can be used as substrates for Morita-Baylis-Hillman reactions. The goal of this subproject is to assess the versatility of a reaction recently developed in our laboratory using vinyl-oxadiazoles in the presence of other vinyl-heterocyclic derivatives.In the fourth subproject, we intend to develop an asymmetric version of the Morita-Baylis-Hillman reaction between isatins and sulfonylimines. There is no precedent in the literature for asymmetric versions of this reaction. The success of this approach should enable access to enantiomerically pure new heterocycles, with significant potential for biological applications and materials chemistry.In the fifth subproject, we intend to continue a project that aims to synthesize chiral lactones exhibiting good antitumor activity, with the goal of discovering new hits with improved antitumor activity against human cancer cell lines and lower toxicity against healthy human cells. (AU)

Scientific publications

(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)

RODRIGUES JR, MANOEL T.; SERAFIM, JOSE CLAUDIO; SANTOS, HUGO; ARANTES, JOAO; SENNA, ANA JULIA; ACCONCIA, LAIS V.; MOYANO, ALBERT; COELHO, FERNANDO. A General Protocol for the Aqueous Morita-Baylis-Hillman Reaction between Cyclic Enones and 1,2-Dicarbonyl Compounds. EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, v. 27, n. 48, p. 9-pg., 2024-12-11. (13/07600-3, 18/02611-0, 17/02364-0, 15/09205-0, 23/18007-3)

RODRIGUES JR, MANOEL T.; DE OLIVEIRA, ALINE S. B.; GOMES, RALPH C.; HIRATA, AMANDA SOARES; ZEOLY, LUCAS A.; SANTOS, HUGO; ARANTES, JOAO; REIS-SILVA, CATARINA SOFIA MATEUS; MACHADO-NETO, JOAO AGOSTINHO; COSTA-LOTUFO, LETICIA VERAS; et al. Bismuth(III) triflate: an economical and environmentally friendly catalyst for the Nazarov reaction. Beilstein Journal of Organic Chemistry, v. 20, p. 12-pg., 2024-05-21. (19/23864-7, 15/09205-0, 23/18007-3, 17/24993-0, 15/17177-6, 13/07600-3, 18/02611-0)