Medicinal Chemistry Research最新文献

Quorum sensing (QS) is the mechanism in which bacteria assess the threshold concentration of small signaling molecules to induce cell survival by overwhelming the host’s defenses. It is one of the fundamental mechanisms controlling bacterial mobility, motility, biofilm formation, and virulence. As many clinically resistant strains bypass traditional antimicrobial medications through this pathway, finding new therapeutics that target QS mechanisms is essential to treat these dangerous pathogens. Marine microbes are a promising source of potential therapeutics and have evolved molecules that can modulate disease-relevant signaling pathways, including QS. Compounds of various biosynthetic origin, including lipopeptides, alkaloids, cyclic peptides, and fatty acids have been shown to modulate QS pathways. In the present work, we have described the isolation, structure characterization, and biological evaluation of two new fatty acids, anaeic acid and tumoic acid. Anaeic acid (3) is a cyclopropanated fatty acid and shorter chain homologue of lyngbyoic acid (1). Tumoic acid (4) is the (6R)-methylated analogue of pitinoic acid A (2), characterized by a C-5 exo-double bond. The configurational assignment of 3 was conducted through analysis of the ¹H and 2D NMR to establish the trans configuration of the cyclopropane ring using the NOE correlations, and optical rotation was used to determine the absolute configuration of 3 compared to 1. The absolute configuration of 4 was established through chemical degradation and derivatization of the liberated secondary alcohol with a chiral auxiliary, followed by Mosher’s ester analysis. Both compounds were compared directly with their close cyanobacterial analogues 1 and 2, distinguished by different chain length and differences in methylation, and their unbranched counterparts to assess the impact of the substitution pattern on functional responses with respect to QS. Compounds 1-4 exhibited moderate QS inhibitory activity against Pseudomonas aeruginosa based on the reduced virulence factor production and transcriptional response. In contrast, unbranched fatty acid counterparts octanoic (5), decanoic acid (6) and lauric acid (7) showed a propensity to activate QS signaling, although this effect was only significantly manifested on the transcriptional level.

[¹¹C]COU is a trapped metabolite radiotracer for in vivo analysis of Monoamine Oxidase B activity using positron emission tomography (PET) imaging. [¹¹C]COU has the potential to quantify astrocytosis in the early stages of Alzheimer’s disease, providing an earlier marker of disease than currently available for staging disease progression. Prior preclinical studies have demonstrated the efficacy of this radiotracer in preclinical imaging studies, warranting the translation for clinical evaluation. In this paper, we describe results of the requisite preclinical studies required to obtain approval for translation of [¹¹C]COU into first-in-human studies. Development and validation of a production method that conforms to the quality requirements described in the US Pharmacopeia was accomplished, along with preclinical rodent studies to determine human radiation dose estimates and a single acute dose pharmacology and toxicology study to establish that an injected mass dose 100-fold higher than the proposed PET imaging dose was below the no-observed-adverse-effect level (NOAEL). The production method was validated in triplicate, yielding [¹¹C]COU in sufficient radiochemical yield (9.3 ± 0.008%), radiochemical purity (99.2 ± 0.002%) and molar activity (165 ± 65 TBq/mmol) for routine clinical use, and providing a product that was sterile and met (or exceeded) all quality control requirements for human use. Dosimetric analysis determined that the effective human dose of [¹¹C]COU is 0.005 mSv/MBq, also acceptable for clinical use. Lastly, no observable adverse effects were noted at 86 μg/kg in rodent toxicology studies (100x the proposed human dose). From these results we received approval to advance [¹¹C]COU into clinical studies.

Lenacapavir is a first-in-class, long-acting HIV-1 capsid inhibitor and represents a significant advancement in both the treatment and prevention of HIV-1 infection. It is highly effective against both wild-type and multidrug-resistant strains of the virus. It has a unique mechanism of action involving the disruption of HIV-1 capsid assembly and nuclear import, which ultimately prevents the virus from integrating its genetic material into the host cell’s DNA and hinders viral replication. This review covers lenacapavir’s discovery and development, with a focus on its target validation, lead optimization, chemical synthesis, pharmacokinetic properties, safety profile, and clinical applications.

The natural product cortistatin A and its derivative didehydro-cortistatin A exhibit potent biological activity in different disease states, indicating the potential utility of their derivatives as treatments for a variety of diseases. The synthesis of the unique ring system found in these compounds is challenging, and therefore we designed analogs with a conventional steroidal scaffold that retained the A-ring functionalities with the stereochemistries found in the natural product, building on a previous report of simplified didehydro-cortistatin A analogs. The steroidal derivatives were synthesized in 9 steps from prednisone with different isoquinoline isomers incorporated at C17 via a Stille coupling in the last step. The analogs exhibited antiproliferative activity in HCT 116 colon cancer cells with low micromolar potency (HCT 116 IC₅₀ = 4.80–11.5 µM) and rapid onset. The methodology described here can be used to prepare additional simplified didehydro-cortistatin A analogs for future biological applications.

Understanding the clearance pathways of drug candidates and the fraction metabolized (f_m) by drug-metabolizing enzymes is a major focus during drug discovery and development process. While selective cytochrome P450 (CYP) inhibitors are widely available, the lack of potent pan- uridine 5’-diphospho-glucuronosyltransferases (UGT) inhibitors with minimal cross-inhibition on CYP enzymes limits the ability to evaluate the contribution of UGT to drug clearance in vitro and in vivo. This study screened five potential inhibitors—triclosan, salicylamide, valproic acid, benzoic acid, and borneol—across twelve human UGT isoforms using human liver microsomes (HLM) and Supersome®. Triclosan emerged as a potent pan-UGT inhibitor, exhibiting IC₅₀ values below 10 µM for all tested isoforms, ranging from 0.43–9.9 µM. However, triclosan also inhibited multiple CYP enzymes with IC₅₀ values ranging from 0.12 to 22 µM. The concurrent inhibition of multiple CYP enzymes limits the application of triclosan as a selective tool compound for UGT reaction phenotyping. The kinetic analysis revealed noncompetitive inhibition of UGT1A3-mediated telmisartan glucuronidation by triclosan, where the other tested compounds failed to inhibit UGT1A3. Notably, triclosan demonstrated high selectivity and potency toward CYP2C19 (IC₅₀ 0.12 µM), suggesting its potential use in CYP2C19 reaction phenotyping in HLM. Additionally, triclosan selectively inhibited flavin-containing monooxygenase 3 (FMO3) but not FMO5.

This study was designed to synthesize a series of carvacrol-based fibrate derivatives based on a molecular hybridization strategy. In acute hyperlipidemic mice, the target compound T7 exhibited a noticeable effect on lowering lipid and demonstrated a dose-dependent characteristic. In the high-fat diet (HFD) mouse model, T7 notably decreased triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels, and elevated high-density lipoprotein cholesterol (HDL-C) levels in both serum and liver tissues. Additionally, T7 appreciably increased the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) found in both serum and liver tissues. Liver histopathological examination indicated that it could inhibit hepatic lipid accumulation and alleviate liver injury. After administration, T7 exhibited anti-oxidative stress and anti-inflammatory effects. It could appreciably increase the activity of superoxide dismutase (SOD), decrease the activity of lipid peroxidation product malondialdehyde (MDA), and appreciably reduce the pro-inflammatory factors interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) levels. Molecular docking experiments demonstrated that T7 exhibited a strong binding affinity with the peroxisome proliferator-activated receptor-α (PPAR-α) receptor. T7 enhanced the PPAR-α expression in liver tissues, indicating that T7 may regulate lipid metabolism by activating the PPAR-α receptor. The hepatoprotective effect of T7 may be closely linked to its capacity to reduce oxidative stress and inflammatory responses. In conclusion, T7 may be a potential novel lipid-lowering candidate compound with the potential to improve liver injury.