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Novel marinoquinoline-based compounds for tuberculosis therapy: design, synthesis and structure-activity screening

Grant number: 16/23055-3
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): February 01, 2017
Effective date (End): January 31, 2018
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Organic Chemistry
Principal researcher:Carlos Roque Duarte Correia
Grantee:Michele Panciera
Supervisor abroad: Concepción González-Bello
Home Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Research place: Universidade de Santiago de Compostela, Santiago (USC), Spain  
Associated to the scholarship:13/25613-5 - Synthesis of molecular fluorescent diarylmaleimide probes form the Heck-Matsuda reactions and their applications in biology and biochemistry, BP.PD

Abstract

The decreased effectiveness of antibacterial agents against infectious diseases caused by the development of drug resistance has become one of the most important public health issues of the early 21st century, making infectious diseases as tuberculosis the second leading cause of death worldwide. The lack of effective antibiotics will undermine our ability to fight infectious diseases and manage the infectious complications common in vulnerable patients. Therefore, it is urgent to search for new drugs and approaches to face the challenge of multidrug resistance. The aim of this proposal is to address key pathogens causing major drug resistance problems by exploring the potential of marinoquinoline derivatives (MQs). These compounds, which contain the 3H-pyrrolo[2,3-c]quinoline unit, has been scarcely studied. However, preliminary biological assays showed that MQs have promising antimicrobial activity. We believe that this class of compounds constitutes an opportunity to investigate the medicinal applicability of such structures prepared by a versatile, short and efficient methodology developed in our group. The biological activity of the already synthesized MQs analogues was substantially enhanced by modification of electronic parameters through the attachment of different substituent to the 3H-pyrrolo[2,3-c]quinoline scaffold. For in vitro assays against protozoa, the natural MQ showed moderate activity at the micromolar scale, whereas some of the unnatural analogues were active in the nanomolar range. In addition, our chemical library proved to have excellent in vitro antibacterial activity against 6 multi-resistant bacterial strains. Moreover, some analogues have good activity against Mycobacterium tuberculosis, although more extensive studies would be appropriate to find a lead compound that would lead to a drug candidate. Due to promising preliminary results and current lack of deeper insights about the structure activity relationship of MQs, we believe that the further investigation of the mechanism of action and the structure activity relationships could lead to MQ analogues with much improved biological and pharmacological activities. (AU)

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