Novel antimalarial drug

A compound, pyrazole technology, applied in the direction of anti-infective drugs, drug combinations, pharmaceutical formulations, etc., can solve problems such as damage to chemotherapy

Pending Publication Date: 2022-08-02
BOARD OF RGT THE UNIV OF TEXAS SYST +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the widespread emergence of drug resistance in malaria parasites in malaria-endemic countri

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0183] Example 1: Synthesis of compounds according to the invention

[0184] The compounds of the present invention can be prepared from readily available starting materials using methods and procedures known to those skilled in the art. It should be understood that where typical or preferred experimental conditions (ie, reaction temperatures, times, moles of reagents, solvents, etc.) are given, other experimental conditions may also be used unless otherwise indicated. Optimal reaction conditions may vary with the particular reactants or solvents used, but these conditions can be determined by one skilled in the art using routine optimization procedures.

[0185] Compounds 1 to 36 of the present invention were synthesized as described in the general synthetic routes described herein. In particular, for compounds of formula (I), when two R 2 When linked to form an optionally substituted cyclopropyl, compounds were synthesized according to Scheme 3 below.

[0186] Scenario 3...

Embodiment 2

[0346] Example 2: Method for Assessing Solubility of Compounds of the Invention

[0347] The solubility and metabolic stability of the compounds of the present invention were assessed according to the protocol detailed in Phillips et al., 2015, supra, and are listed in Table 1 below, in comparison to DSM 265 having the following structure:

[0348]

[0349] Table 1

[0350]

[0351]

[0352] These data support the significantly improved solubility of the compounds of the present invention over DSM265. In addition, compound 14 is particularly stable in metabolism.

Embodiment 3

[0353] Example 3: The activity of the compound against Plasmodium and mammalian DHODH indicates that the compound is effective against Plasmodium enzymes selective activity.

[0354] Protein expression and purification. Contains His 6 BL21-DE3 E. coli labeled DHODH-pRSETb (N-terminal tag) (Pf and PvDHODH), pET22b C-terminal tag (human) or pET-28b C-terminal tag (rat, mouse and dog) constructs (E coli) phage-resistant cells were cultured and harvested with appropriate antibiotics, and proteins were purified using HisTrap HP columns, followed by gel filtration as previously described (Coteron et al., 2011, J.Med Chem), Vol. 54, No. 15, pp. 5540-5561; Phillips et al., 2015, supra; White et al., 2019, ACS Infect Dis, Vol. 5, No. 1 , pp. 90-101). The concentration of purified DHODH was determined based on FMN absorbance at 454 nm (ε445 = 12.5 mM -1 cm -1 ) (Malmquist et al., 2008, Biochemistry, Vol. 47, No. 8, pp. 2466-2475).

[0355] DHODH kinetic analysis. The 50% inhi...

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PUM

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Abstract

The present invention relates to novel pyrrole derivatives in the preparation of medicaments for the prevention or treatment of malaria. In particular, the present invention relates to pyrrole derivatives for the preparation of pharmaceutical preparations for inhibiting malaria parasite proliferation.

Description

technical field [0001] The present invention relates to new antimalarial drugs. In particular, the present invention relates to medicaments for the preparation of pharmaceutical preparations for the prevention or treatment of malaria and methods of their use and preparation. Background technique [0002] Malaria is caused by protozoan parasites of the genus Plasmodium, which infect and destroy red blood cells, resulting in fever, severe anemia, cerebral malaria and, if untreated, death. Plasmodium falciparum is the dominant species in sub-Saharan Africa, killing nearly 1 million people each year. In Africa, children under the age of 5 and pregnant women have the highest disease burden. Plasmodium vivax is responsible for 25-40% of the global malaria burden, especially in South and Southeast Asia and Central and South America. The other three major species known to infect humans are Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi. [0003] Malaria is a dise...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D403/12C07D413/14A61K31/4439A61K31/4196A61P33/06C07D207/34
CPCC07D401/14C07D403/12C07D413/14A61P33/06A61K31/357A61K31/366A61K31/4162A61K31/4196A61K31/4439A61K31/4706C07D207/34Y02A50/30A61K2300/00A61K31/122A61K31/137A61K31/155A61K31/4709A61K31/473A61K31/4745A61K31/65
Inventor M·菲利普斯M·帕尔默S·A·查曼K·S·瓦特A·I·杰拉修托G·克里洛夫
Owner BOARD OF RGT THE UNIV OF TEXAS SYST
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