Route exploration and synthesis of the reported pyridone-based PDI inhibitor STK076545.
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ABSTRACT:
SUBMITTER: Greve E
PROVIDER: S-EPMC7899705 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In this study, a novel pyridone-based phthalimide fleximer, that is, ethyl 5-cyano-6-(3-(1,3-dioxoisoindolin-2-yl)propoxy)-4-(3-methoxyphenyl)-2-methylnicotinate, was synthesized, and its structure was established by the single-crystal X-ray diffraction method. The supramolecular self-assembly of the titled compound through noncovalent interactions was then investigated thoroughly. The titled compound crystallized with two symmetry-independent molecules (A and B, Z' = 2). In agreement with experimental observations, our density functional theory calculations also showed that the titled compound has a flexible motif and can occur in various conformations, including molecules A and B. The investigation of the supramolecular framework revealed that the molecules are notably bound by the nonclassical C-H···O and C-H···N hydrogen bonds and C-H···π interactions. Hirshfeld surface analysis was carried out to quantify the various intermolecular interactions. The dual anti-inflammatory activity of the tilted compound was also explored by molecular docking in the active sites of 5-LOX and COX-2 receptors, which revealed good binding affinities of -9.0 and -8.6 kcal/mol, respectively.
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Project description:Chlamydia trachomatis is a strict intracellular bacterium that causes sexually transmitted infections and eye infections that can lead to life-long sequelae. Treatment options are limited to broad-spectrum antibiotics that disturb the commensal flora and contribute to selection of antibiotic-resistant bacteria. Hence, development of novel drugs that specifically target C. trachomatis would be beneficial. 2-pyridone amides are potent and specific inhibitors of Chlamydia infectivity. The first generation compound KSK120, inhibits the developmental cycle of Chlamydia resulting in reduced infectivity of progeny bacteria. Here, we show that the improved, highly potent second-generation 2-pyridone amide KSK213 allowed normal growth and development of C. trachomatis and the effect was only observable upon re-infection of new cells. Progeny elementary bodies (EBs) produced in the presence of KSK213 were unable to activate transcription of essential genes in early development and did not differentiate into the replicative form, the reticulate body (RB). The effect was specific to C. trachomatis since KSK213 was inactive in the closely related animal pathogen C. muridarum and in C. caviae The molecular target of KSK213 may thus be different in C. trachomatis or non-essential in C. muridarum and C. caviae Resistance to KSK213 was mediated by a combination of amino acid substitutions in both DEAD/DEAH RNA helicase and RNAse III, which may indicate inhibition of the transcriptional machinery as the mode of action. 2-pyridone amides provide a novel antibacterial strategy and starting points for development of highly specific drugs for C. trachomatis infections.
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Project description:UnlabelledIn a screen for compounds that inhibit infectivity of the obligate intracellular pathogen Chlamydia trachomatis, we identified the 2-pyridone amide KSK120. A fluorescent KSK120 analogue was synthesized and observed to be associated with the C. trachomatis surface, suggesting that its target is bacterial. We isolated KSK120-resistant strains and determined that several resistance mutations are in genes that affect the uptake and use of glucose-6-phosphate (G-6P). Consistent with an effect on G-6P metabolism, treatment with KSK120 blocked glycogen accumulation. Interestingly, KSK120 did not affect Escherichia coli or the host cell. Thus, 2-pyridone amides may represent a class of drugs that can specifically inhibit C. trachomatis infection.ImportanceChlamydia trachomatis is a bacterial pathogen of humans that causes a common sexually transmitted disease as well as eye infections. It grows only inside cells of its host organism, within a parasitophorous vacuole termed the inclusion. Little is known, however, about what bacterial components and processes are important for C. trachomatis cellular infectivity. Here, by using a visual screen for compounds that affect bacterial distribution within the chlamydial inclusion, we identified the inhibitor KSK120. As hypothesized, the altered bacterial distribution induced by KSK120 correlated with a block in C. trachomatis infectivity. Our data suggest that the compound targets the glucose-6-phosphate (G-6P) metabolism pathway of C. trachomatis, supporting previous indications that G-6P metabolism is critical for C. trachomatis infectivity. Thus, KSK120 may be a useful tool to study chlamydial glucose metabolism and has the potential to be used in the treatment of C. trachomatis infections.
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