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Synthesis of substituted 5H-pyrrolo[3,2-d]pyrimidine derivatives with antimycobacterial activity

Authors: Vrbický Martin | Bartáček Jan | Kocúrik Martin | Finger Vladimír | Roh Jaroslav | Drabina Pavel

Year: 2022

Type of publication: ostatní - přednáška nebo poster

Page from-to: nestránkováno

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Language	Name	Abstract	Keywords
eng	Synthesis of substituted 5H-pyrrolo[3,2-d]pyrimidine derivatives with antimycobacterial activity	Tuberculosis (TB) is a communicable disease caused mainly by the bacillus Mycobacterium tuberculosis. In 2019, WHO reported 10 million new TB cases and about 1.4 million TB deaths. With approximately a quarter of the world’s population infected by M. tuberculosis, TB remains among the top 10 lethal diseases worldwide.1 Incorrect treatment and low availability of medication led to the formation of resistant strains. Isoniazid and rifampicin, the most clinically successful anti-TB drugs, had paradoxically became a defining focus of the current multidrug-resistant and extensively drug-reInitial research of our colleagues in Hradec Králové identified compound with good anti-TB activity with minimum inhibitory concentration MIC99 = 4 μM against H37Rv strain (for comparison, MIC99 (Isoniazid) = 0.5 μM). The main structural motif of this molecule was purine scaffold. Pilot series of analogues of this substance then showed relationships between structure and activity, especially the role of substitution in positions 7 and 9. Majority of purine derivatives with anti-TB activity known from the literature are substituted in position 9. Position 7 is rare and it assumes not only great potential for its development but also different mechanism of action. Good anti-TB activity was unfortunately accompanied by low synthesis efficiency. Hence, we decided to replace original motif by 5H-pyrrolo[3,2- d]pyrimidine, which was modified and functionalized to elucidate the structure-activity relationships (SAR) and to identify derivatives with low toxicity and higher efficiency than the initial molecule. The effect of individual structural fragments on in vitro antimycobacterial activity, toxicity and selectivity of action have been evaluated. Finally, derivatives with optimized activity/toxicity ratio have been found and their pharmacokinetic profile and in vivo efficacy will be evaluated.sistant epidemic.2 Therefore, the development of new anti-TB drugs with new mechanism of action is n	5H-pyrrolo3,2-dpyrimidine; antimycobacterial activity; tuberculosis