SAR study of N'-(Salicylidene)heteroarenecarbohydrazides as promising antifungal agents.

Clinically available antifungal drugs have therapeutic limitations due to toxicity, narrow spectrum of activity, and intrinsic or acquired drug resistance. Thus, there is an urgent need for new broad-spectrum antifungal agents with low toxicity and a novel mechanism of action. In this context, we have successfully identified several highly promising lead compounds, i.e., aromatic N'-(salicylidene)carbohydrazides, exhibiting excellent antifungal activities against Cryptococcus neoformans, Candida albicans, Aspergillus fumigatus and several other fungi both in vitro and in vivo. Building upon these highly promising results, 71 novel N'-(salicylidene)heteroarenecarbohydrazides 5 were designed, synthesized and their antifungal activities examined against fungi. Based on the SAR study, four highly promising lead compounds, i.e., 5.6a, 5.6b, 5.7b and 5.13a were identified, which exhibited excellent potency against C. neoformans, C. albicans and A. fumigatus, and displayed impressive time-kill profiles against C. neoformans with exceptionally high selectivity indices (SI ≥ 500). These four lead compounds also showed synergy with clinical antifungal drugs, fluconazole, caspofungin (CS) and amphotericin B against C. neoformans. For the SAR study, we also employed quantitative structure-activity relationship (QSAR) analysis by taking advantage of the accumulated data on a large number of aromatic and heteroaromatic N'-(salicylidene)carbohydrazides, which successfully led to rational design and selection of promising compounds for chemical synthesis and biological evaluation.

Truxillic acid monoamides as fatty acid binding protein 5 inhibitors.

Fatty acid binding proteins (FABPs) are intracellular chaperones that deliver bioactive lipids to cytosolic enzymes and nuclear receptors, thereby regulating diverse biological functions. FABP5 is a member of the FABP family that mediates endocannabinoid transport and inactivation, with pharmacological or genetic FABP5 inhibition conferring antinociceptive effects. Consequently, FABP5 inhibitors have emerged as promising analgesics and demonstrate antinociceptive activity in models of pain. Recently developed FABP5 inhibitors based upon the α-truxillic acid monoester (TAME) scaffold demonstrate high affinities for FABP5 but are commonly accompanied by reduced selectivity against related FABPs, notably FABP3 that is expressed in the heart, highlighting the need to identify additional scaffolds that afford enhanced selectivity while maintaining FABP5 potency. Here, we describe the synthesis and biological evaluation of truxillic acid monoamides (TAMADs) as potent, selective, and efficacious FABP5 inhibitors. Combining in silico molecular docking and in vitro binding assay approaches, our findings demonstrate that TAMADs exhibit exceptional selectivity against FABP3 and several compounds attain high FABP5 affinities. Examination of antinociceptive activity revealed that TAMADs and their corresponding TAMEs demonstrate comparable efficacy and temporal activity profiles in vivo. These results position TAMAD as a suitable scaffold for the development of FABP5 inhibitors with diminished FABP3 cross-reactivity.

Enhanced Photoacoustic Detection of Heparin in Whole Blood via Melanin Nanocapsules Carrying Molecular Agents.

Photoacoustic (PA) imaging has proved versatile for many biomedical applications from drug delivery tracking to disease diagnostics and postoperative surveillance. It recently emerged as a tool for accurate and real-time heparin monitoring to avoid bleeding complications associated with anticoagulant therapy. However, molecular-dye-based application is limited by high concentration requirements, photostability, and a strong background hemoglobin signal. We developed polydopamine nanocapsules (PNCs) via supramolecular templates and loaded them with molecular dyes for enhanced PA-mediated heparin detection. Depending on surface charge, the dye-loaded PNCs undergo disassembly or aggregation upon heparin recognition: both experiments and simulation have revealed that the increased PA signal mainly results from dye-loaded PNC-heparin aggregation. Importantly, Nile blue (NB)-loaded PNCs generated a 10-fold higher PA signal than free NB dye, and such PNC enabled the direct detection of heparin in a clinically relevant therapeutic window (0-4 U/mL) in whole human blood (R2 = 0.91). Furthermore, the PA signal of PNC@NB obtained from 17 patients linearly correlated with ACT values (R2 = 0.73) and cumulative heparin (R2 = 0.83). This PNC-based strategy for functional nanocapsules offers a versatile engineering platform for robust biomedical contrast agents and nanocarriers.