Unleashing the potential of vanillic acid: A new twist on nature's recipe to fight inflammation and circumvent azole-resistant fungal infections.

Vanillic acid (VA) - a naturally occurring phenolic compound in plants - is not only used as a flavoring agent but also a prominent metabolite post tea consumption. VA and its associated compounds are believed to play a significant role in preventing diseases, underscoring the need for a systematic investigation. Herein, we report a 4-step synthesis employing the classical organic reactions, such as Willamson's alkylation, Fischer-Spier reaction, and Steglich esterification, complemented with a protection-deprotection strategy to prepare 46 VA derivatives across the five series (1a-1i, 2a-2i, 3, 3a-3i, 4a-4i, 5a-5i) in high yields. The synthesized compounds were investigated for their antifungal, anti-inflammatory, and toxic effects. Notably, compound 1a demonstrated remarkable ROS inhibition with an IC50 value of 5.1 ± 0.7 µg/mL, which is more than twice as effective as the standard ibuprofen drug. A subset of the synthesized derivatives (2b, 2c, 2e, 3b-3d, 4a-4c, 5a, and 5e) manifested their antifungal effect against drug-resistant Candida strains. Compound 5g, in particular, revealed synergism with the established antifungal drugs amphotericin B (AMB) and fluconazole (FLZ), doubling FLZ's potency against azole resistant Candida albican ATCC 36082. Furthermore, 5g improved the potency of these antifungals against FLZ-sensitive strains, including C. glabrata ATCC 2001 and C. parapsilosis ATCC 22019, as well as various multidrug-resistant (MDR) Candida strains, namely C. albicans ATCC 14053, C. albicans CL1, and C. krusei SH2L OM341600. Additionally, pharmacodynamics of compound 5g was examined using time-kill assay, and a benign safety profile was observed with no hemolytic activity in whole blood, and no cytotoxicity towards the normal BJ human cell line. The synergistic potential of 5g was further investigated through both experimental methods and docking simulations.These findings highlight the therapeutic potential of VA derivatives, particularly in addressing inflammation and circumventing FLZ resistance in Candida albicans.

In vitro photoprotective potential of aryl-sandwiched (thio)semicarbazones against UVA mediated cellular and DNA damage.

The most prevalent solar ultraviolet radiation is ultraviolet-A (UVA) radiation. It is the inducer of reactive oxygen species (ROS), a potent mediator of inflammation and photocarcinogenesis. Regular application of sunscreens containing UVA filters is an effective preventive measure in mitigating the risk associated with the formation of dermal carcinoma. Therefore, the development of new photoprotective agents is of great need. The current work examined the in vitro photoprotection of the aryl-linked (thio)semicarbazone derivatives against UVA-mediated DNA damage, inflammation, reactive nitrogen species (RNS), and ROS. Except for the inflammatory cytokine assay, which was carried out on the human monocytic leukemia (THP-1) cell line, all tests were conducted on the human dermal fibroblast (BJ) cell line. In comparison to benzophenone (reference compound), the compound (2Z, 2'Z)-2,2'-(1,3-Phenylenebis (methanylylidene)) bis (hydrazine-1-carbothioamide) (DD-21) demonstrated considerable protection against UVA-induced damage. Compared to the UVA-irradiated control, DD-21 significantly decreased the levels of nitric oxide (NO) and ROS (p < 0.001). In the presence of DD-21, the release of UVA-induced pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), was also significantly reduced (p < 0.05). Moreover, it was observed that DD-21 protected the cells from UVA-mediated DNA strand breaks and also inhibited the formation of cyclobutane pyrimidine dimers (CPDs) upon comparison to the UVA-exposed control cells (p < 0.001). In conclusion, the findings of this study revealed that DD-21 exhibits remarkable photoprotective properties, thus demonstrating its potential as a candidate UVA filter.

Probing photoprotection properties of lipophilic chain conjugated thiourea-aryl group molecules to attenuate ultraviolet-A induced cellular and DNA damages.

Ultraviolet-A (UVA) radiation is a major contributor to reactive oxygen species (ROS), reactive nitrite species (RNS), inflammation, and DNA damage, which causes photoaging and photocarcinogenesis. This study aimed to evaluate the UVA protective potential of lipophilic chain conjugated thiourea-substituted aryl group molecules against UVA-induced cellular damages in human dermal fibroblasts (BJ cell line). We tested a series of nineteen (19) molecules for UVA photoprotection, from which 2',5'-dichlorophenyl-substituted molecule DD-04 showed remarkable UVA protection properties compared to the reference (benzophenone). The results indicate that DD-04 significantly reduced intracellular ROS and nitric oxide (NO) as compared to the UVA-irradiated control (p < 0.001). Moreover, the compound DD-04 showed anti-inflammatory activity as it significantly reduced the levels of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) pro-inflammatory cytokines produced by THP-1 (human monocytic) cells (p < 0.05). DNA damage was also prevented by DD-04 treatment in the presence of UVA. It was observed that DD-04 significantly reduced the number of cyclobutane pyrimidine dimers (CPDs) when compared to the UVA-irradiated control (p < 0.001). Finally, the DNA strand breaks were checked and a single intact DNA band was seen upon treatment with DD-04 in the presence of UVA. In conclusion, DD-04 can be considered a potential candidate UVA filter due to its photoprotective potential.

Antiurease screening of alkyl chain-linked thiourea derivatives: in vitro biological activities, molecular docking, and dynamic simulations studies.

Urease has become an important therapeutic target because it stimulates the pathogenesis of many human health conditions, such as pyelonephritis, the development of urolithiasis, hepatic encephalopathy, peptic ulcers, gastritis and gastric cancer. A series of alkyl chain-linked thiourea derivatives were synthesized to screen for urease inhibition activity. Structure elucidation of these compounds was done by spectral studies, such as IR, 1H NMR and 13C NMR, and MS analysis. In vitro urease enzyme inhibition assay revealed that compound 3c was the most potent thiourea derivative among the series with IC50 values of 10.65 ± 0.45 µM, while compound 3g also exhibited good activity with an IC50 value of 15.19 ± 0.58 µM compared to standard thiourea with an IC50 value of 15.51 ± 0.11 µM. The other compounds in the series possessed moderate to weak urease inhibition activity with IC50 values ranging from 20.16 ± 0.48 to 60.11 ± 0.78 µM. The most potent compounds 3c and 3g were docked to jack bean urease (PDB ID: 4H9M) to evaluate their binding affinities and to find the plausible binding poses. The docked complexes were refined through 100 ns-long MD simulations. The simulation results revealed that the average RMSD of 3c was less than that of the 3g compound. Furthermore, the radius of gyration plots for both complexes showed that 3c and 3g docking predicted binding modes did not induce any conformational change in the urease structure.

Designing Functionally Substituted Pyridine-Carbohydrazides for Potent Antibacterial and Devouring Antifungal Effect on Multidrug Resistant (MDR) Strains.

The emergence of multidrug-resistant (MDR) pathogens and the gradual depletion of available antibiotics have exacerbated the need for novel antimicrobial agents with minimal toxicity. Herein, we report functionally substituted pyridine carbohydrazide with remarkable antimicrobial effect on multi-drug resistant strains. In the series, compound 6 had potent activity against four MDR strains of Candida spp., with minimum inhibitory concentration (MIC) values being in the range of 16-24 µg/mL and percentage inhibition up to 92.57%, which was exceptional when compared to broad-spectrum antifungal drug fluconazole (MIC = 20 µg/mL, 81.88% inhibition). Substitution of the octyl chain in 6 with a shorter butyl chain resulted in a significant anti-bacterial effect of 4 against Pseudomonas aeruginosa (ATCC 27853), the MIC value being 2-fold superior to the standard combination of ampicillin/cloxacillin. Time-kill kinetics assays were used to discern the efficacy and pharmacodynamics of the potent compounds. Further, hemolysis tests confirmed that both compounds had better safety profiles than the standard drugs. Besides, molecular docking simulations were used to further explore their mode of interaction with target proteins. Overall results suggest that these compounds have the potential to become promising antimicrobial drugs against MDR strains.

Synthesis of Highly Potent Anti-Inflammatory Compounds (ROS Inhibitors) from Isonicotinic Acid.

In search of anti-inflammatory compounds, novel scaffolds containing isonicotinoyl motif were synthesized via an efficient strategy. The compounds were screened for their in vitro anti-inflammatory activity. Remarkably high activities were observed for isonicotinates 5-6 and 8a-8b. The compound 5 exhibits an exceptional IC50 value (1.42 ± 0.1 µg/mL) with 95.9% inhibition at 25 µg/mL, which is eight folds better than the standard drug ibuprofen (11.2 ± 1.9 µg/mL). To gain an insight into the mode of action of anti-inflammatory compounds, molecular docking studies were also performed. Decisively, further development and fine tuning of these isonicotinates based scaffolds for the treatment of various aberrations is still a wide-open field of research.