Fused Bicyclic Pyridine Compounds for Pathogen G-Quadruplex Targeting
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Solution Overview
Problem
Current treatments for infectious diseases, particularly those caused by parasites and viruses, face challenges due to drug resistance and the lack of effective antimalarial, antiviral, and antiprotozoal compounds, with existing G-quadruplex-stabilizing drugs showing limited efficacy against emerging pathogens like Plasmodium falciparum, Leishmania, Trypanosoma, and SARS-CoV-2.
Innovation Solution
Development of 6-6 or 5-6 fused bicyclic compounds comprising pyrimidine or pyridine that specifically target G-quadruplex structures in pathogens, interfering with their replication and transcription processes, thereby exhibiting antimalarial, antitrypanosomal, and antiviral activities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing G-quadruplex-stabilizing drugs are used, then some antiparasitic and antiviral activity is achieved, but drug resistance develops and efficacy is limited against emerging pathogens
Solution Approach 1:
The patent modifies the chemical structure of G-quadruplex-stabilizing compounds by changing parameters such as the core heterocyclic structure (pyrimidine, pyridine rings), substituent groups, and molecular geometry to create new derivatives with improved activity against drug-resistant and emerging pathogens including Plasmodium falciparum, Leishmania, Trypanosoma, and SARS-CoV-2
2Reliability
If new antimalarial and antiviral compounds are developed, then efficacy against emerging pathogens is improved, but drug toxicity may increase
Solution Approach 1:
The patent introduces specific functional groups and substituent patterns at particular positions on the bicyclic core structure to enhance pathogen-specific targeting while minimizing interaction with human cellular components, thereby improving selectivity and reducing cytotoxicity
Solution Approach 2:
The patent employs structurally simple bicyclic compounds with modular substituent groups that can be readily synthesized and modified, allowing for rapid optimization of the therapeutic window between effective antiparasitic/viral activity and cytotoxicity levels
Data Source
AI summary
The present invention relates to new specific 6-6 or 5-6 fused bicyclic compounds comprising pyrimidine or pyridine useful in the prevention and/or treatment of infectious diseases. In particular, the present invention relates to a compound of formula (I) wherein: Ar1 is a (C5-C11)arylene or (C5-C11)heteroarylene group, X is —CH—, —S—, —NR5 or —N—, Y is —CH—, —NR5—S— or —NR6—CH2—, T is —CH— and Q is —CH— or T is —N— and Q is —CR10— or —N—, provided that one or two of X, Q and Y comprise a heteroatom, and with the proviso that, at least one of R1, R2, and, if present, R5 or R6, contains a group —NH-Alk-NR3R4. The inventors showed that compounds of formula (I) present an activity against both W2 and 3D7 Plasmodium falciparum strains, an activity against T. brucei brucei but also an activity against SARS-CoV-2 virus, and that they are positive for G4 recognition. The invention also relates to the preparation process and to the therapeutic uses of the compounds of formula (I).