engleski

NOVEL ANTHRANILIC ACID DERIVATIVES AS PROMISING ANTI-TB AGENTS

Tuberculosis (TB) is still one of the top 10 causes of death, based on the WHO 2020 report (1), although much effort has been dedicated to the development of new anti-TB agents. After the discovery of bedaquilline, the quinoline heterocycle was recognized as a promising scaffold in search of new anti-TBC drugs. Inspired by this fact, our research team developed a new series of primaquine (PQ) derivatives showing high antitubercular activity (2). Additionally, a recent study involving 1280 fragment-library revealed a fragment from the anthranilic acid series as a lead to develop small molecules that inhibit Mycobacterium tuberculosis MabA activity (3). Bearing this in mind, we have synthesized 19 novel anthranilamides, hybrid compounds bearing chloroquine (CQ), PQ or harmine (HA) moiety in the amine part, and anthranilic derivatives in the carboxylic part of the molecule. The synthesis is outlined in the Scheme. The first step involved the coupling of PQ/CQ/HA with anthranilic acid moiety in the presence of HATU/DIEA or T3P/TEA and the second step was the removal of the protecting group. The Boc-protecting group was removed in the presence of TFA, whereas the benzyl group was removed by catalytic hydrogenation or with ammonium formate. The structures of novel compounds were confirmed by 1H and 13C NMR, IR, and MS spectroscopy. Antimycobacterial evaluation is in progress.

tuberculosis ; chloroquine ; anthranilic acid ; quorum sensing

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