CF3-Pyrimidinone Derivatives Targeting PfPl3K Kinase

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Solution Overview

Problem

Current antimalarial drugs face challenges due to increasing resistance among Plasmodium falciparum strains, necessitating novel compounds with a distinct mode of action to minimize cross-resistance, while inhibiting human kinases can lead to undesirable side effects.

Innovation Solution

Development of CF3-pyrimidinone derivatives that specifically target Plasmodium falciparum kinases, such as PfPl3K, without inhibiting human kinases, thereby offering a novel therapeutic approach for malaria treatment with reduced risk of side effects.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional antimalarial drugs (chloroquine, mefloquine, artemisinin) are used to treat Plasmodium falciparum malaria, then treatment effectiveness is maintained initially, but resistance develops over time rendering them ineffective

Engineering Contradiction:

Improvetreatment effectivenessVSAvoiddrug efficacy duration

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent introduces a novel chemical structure (pyrimidinone derivative with specific CF3 substitution pattern) that represents a fundamental parameter change from existing antimalarial drug classes. This structural innovation targets a different biochemical pathway (PfPl3K kinase) compared to conventional drugs, thereby overcoming resistance mechanisms that have developed against traditional treatments.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention focuses on targeting a specific kinase enzyme (PfPl3K) within the parasite's kinome, representing a segmented approach rather than broad-spectrum inhibition. By selectively inhibiting this particular kinase involved in hemoglobin trafficking and endocytosis, the drug achieves antimalarial activity through a discrete, targeted mechanism that differs from conventional approaches.

Inventive Principle:

Principle #1Segmentation

2Reliability

If human Pl3K inhibitors are developed as antimalarial agents, then parasite growth is inhibited, but side effects occur due to inhibition of human kinases

Engineering Contradiction:

Improveparasite growth inhibitionVSAvoidside effects from human kinase inhibition

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent achieves selective inhibition by designing a molecule with specific local chemical features (CF3-pyrimidinone core with particular substituent patterns) that confer preference for the plasmodial kinase active site over human kinase active sites. This local structural differentiation enables selective binding to PfPl3K while sparing human Pl3K enzymes, thereby inhibiting parasite growth without causing the side effects associated with human kinase inhibition.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The compound acts as a selective intermediary that bridges the gap between needing to inhibit parasite kinases and avoiding human kinase inhibition. The specific molecular structure serves as a mediator that recognizes and binds to the plasmodial kinase with high affinity while having low affinity for human kinases, thus achieving the desired therapeutic effect without the harmful side effects.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentEP2870156B1Pyrimidinone derivatives as antimalarial agents

Publication Date: 2020.06.17 SANOFI SA(FR)

AI summary

The invention relates to novel pyrimidinone-based heterocyclic compounds which are parasite growth inhibitors, having the general formula (I) in which Y is a morpholine chosen from three bridged morpholines, L is a bond or a linker, n = 0 or 1 and R2 is a methyl group when n = 0 and a hydrogen atom when n = 1. Process for the preparation thereof and therapeutic use thereof.