SUMOylation is a critical post-translational modification pathway implicated in various ailments, such as diabetes, neurodegenerative disorders, infectious diseases, and cancer. Dysregulation of SUMOylation affects different hallmarks of cancer, including metastasis, angiogenesis, invasion, and proliferation, making it an important therapeutic target. While anacardic acid (AA) has been shown to inhibit the essential SUMO E1 enzyme (IC50 = 2.1 μM), its clinical potential is limited by high lipophilicity and poor bioavailability, stemming primarily from its C15 alkyl chain. This study is therefore aimed at identifying AA derivatives with improved druggability. Using Mcule, 129 AA derivatives were generated and subjected to molecular docking against SUMO E1, which yielded 61 potential inhibitors based on binding energy. Subsequent virtual screening with SwissADME evaluated their pharmacokinetic properties (solubility, logP, and toxicity), narrowing the candidates to 24 hits. Further analysis identified 2-hydroxy-6-methylbenzoic acid as the top lead compound, demonstrating a superior pharmacokinetic profile. Molecular dynamics simulation studies confirmed its stable binding to SUMO E1 through favorable hydrogen bonding. Previous studies from our laboratory have shown AA to regulate the EGF pathway by inhibiting MMPs directly as well as through its modulators, BSG and TIMP. Based on these observations, GPS SUMO analysis demonstrated potential SUMOylation sites in both BSG and TIMP, which have the potential to be modulated by the lead compound, resulting in regulation of the EGF pathway, thereby controlling cancer progression. These observations strongly support the development of 2-hydroxy-6-methylbenzoic acid and its analogues as potent SUMO E1 inhibitors with enhanced pharmacokinetic profiles for cancer therapy.

Candida albicans is a deadly fungal pathogen, particularly in immunocompromised individuals, where a simple superficial infection rapidly transforms into life-threatening systemic candidiasis. Virulence factors of C. albicans include the yeast-to-hyphae transition, biofilm formation, and protease production, which are crucial for establishing infection. Targeting virulence factors is a promising strategy to combat C. albicans infections, which can overcome the limitations of conventional treatment modalities. Essential oils are important in this regard as they are used in traditional medicine due to their antimicrobial capabilities. This study is focused on the antivirulent activity of cumin essential oil (CEO), which significantly reduced the key virulence factors of C. albicans, such as germ tube formation and protease production. A subinhibitory concentration (0.015% v/v) of CEO downregulated the expression of the HWP1, ALS3, and RAS1 genes involved in regulating virulence. In silico studies demonstrated that major compounds of CEO interacted with key amino acid residues of secreted aspartyl proteases (Sap4, Sap5, Sap6) and heat shock protein (Hsp90), a regulator of hyphal formation. CEO significantly reduced biofilm formation of C. albicans in different simulated body fluids such as saliva, artificial urine, and tear fluid. Furthermore, CEO affected the host–pathogen interaction of C. albicans with THP-1 macrophages by increasing phagocytosis and inhibiting germ tube formation. Additionally, CEO treatment modulated the levels of pro-inflammatory and anti-inflammatory cytokines, suggesting that CEO also has immunomodulatory properties, in addition to its antivirulence activity. These results indicate that CEO could be a promising candidate for combating C. albicans infections.

This study details the design, synthesis, and evaluation of a novel series of fourteen 2-((1H-1,2,4-triazol-5-yl)thio)-N-benzylidene-N-arylacetohydrazide hybrid compounds. The primary objective was to investigate their potential as antimicrobial agents and assess their cytotoxicity. A systematic approach combining in silico screening and experimental validation was employed. The initial in silico analysis, using SwissADME, identified compounds with favorable drug-like properties. Subsequently, all fourteen compounds were synthesized and characterized using various spectroscopic methods. Their antibacterial efficacy was evaluated in vitro against Gram-negative (Klebsiella aerogenes) and Gram-positive (Enterococcus sp.) bacteria through growth kinetics and colony-forming unit (CFU) assays. Cytotoxicity was assessed using MTT assays on HEK (human embryonic kidney) cell lines. The compound, 2-((1H-1,2,4-triazol-3-yl)thio)-N′-(2-fluorobenzylidene)-N-phenylacetohydrazide emerged as the most promising candidate, demonstrating broad-spectrum antibacterial activity. These findings highlight the potential of 2-((1H-1,2,4-triazol-5-yl)thio)-N-benzylidene-N-arylacetohydrazide hybrids as a scaffold for developing new antimicrobial agents. Furthermore, this study suggests possible environmental applications for these compounds in antimicrobial resistance (AMR) management.