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• New methylthiourea-thiophene, -thiazole, or -pyrazole conjugates were synthesized and characterized. • DFT calculations disclosed that synthesized derivatives were nonplanar. • The resulted FMO's energies indicated that all the hybrids have little energy gap. • In-depth molecular docking was explored against the bacterial protein PDB ID 1AJ6. • Methylthiourea-conjugates may exhibit interaction owing to CYP450 isoform inhibition. A series of new functionalized thiophene, thiazole, and pyrazole conjugates with methylthiourea was synthesized by cyclization of 1-(4-(2-bromoacetyl)phenyl)-3-methylthiourea (1) with different thioacetanilides, aryl carbamodithioates, and hydrazonoyl cyanide reagents, respectively. The DFT/B3LYP method showed that the thiazole derivatives 5a–c had lower HOMO-LUMO energies and ΔE H-L than the thiophenes 3a–c and the pyrazoles 7a–c. The synthesized conjugates were examined to investigate their potential as antibacterial agents. Analogue 3a was found to be extremely effective against Gram-positive bacteria by rigorous biological screening, while analogues 3c and 7a were found to be effective against Gram-negative bacteria. Antifungal tests revealed that analogues 3c and 5b were very effective. Molecular docking studies of the bacterial protein PDB ID 1AJ6 showed that analogues 3b and 7b bind most strongly. This suggests that they have important interactions through hydrogen bonds and π-interactions that keep the ligand-receptor complex together. Interestingly, analogue 7b not only demonstrated the highest binding affinity but also excellent structural compatibility with the protein target, establishing it as a lead molecule for further investigation. Despite their promising pharmacological qualities, all analogues faced pharmacokinetic challenges such as poor gastrointestinal absorption and blood-brain barrier permeability. Analogue 3c , for instance, demonstrated a balance between lipophilicity and a lower Topological polar surface area (TPSA) value (113.49 Ų) that supports good gastrointestinal absorption while having poor projected bioavailability, according to Swiss-ADME. [ABSTRACT FROM AUTHOR]

The growing interest in the health and pharmaceutical industries has led to a significant increase in demand for essential oils. Curcuma caesia , as a member of the Zingiberaceae family, has been used for its high-quality essential oils (EOs) with remarkable therapeutic properties. The current study aimed at predicting the in-silico interactions of C. caesia volatile constituents against the protein responsible for oxidative and microbial stress in order to investigate their potential for industrial and pharmaceutical applications. The accuracy of the in-silico predictions was confirmed by carrying out the in vitro validation of the antioxidant, antibacterial, and antifungal activity of the EOs derived from the rhizome and leaves, as well as its volatile constituents. EOs from the rhizome and leaf samples of C. caesia were extracted through the hydro distillation method and yielded a percentage (%) of 1.80 ± 0.02 and 0.95 ± 0.02 (fresh weight basis, v/w), respectively. A total of 38 and 29 volatile constituents were identified in the rhizome and leaf EOs by gas-chromatography mass spectrometry analysis, representing 92.55% and 90.75% of the total peak area, respectively. The rhizome and leaf EOs showed oxygenated sesquiterpene (39.91% and 27.69%) as the predominate fractions followed by sesquiterpene hydrocarbons (13.36% and 18.44%). Curzerenone (18.09%), epicurzerenone (12.47%), eucalyptol (11.57%), camphor (5.94%), and germacrone (4.47%) were the major constituents in the rhizome EO, whereas, the leaf EO was dominated by eucalyptol (12.53%), camphor (7.23%), curzerenone (5.24%), germacrone (4.81%) and curzerene (4.9%). The in vitro biological activities such as antioxidant, antibacterial, and antifungal potential of C. caesia EOs were evaluated. The antioxidant evaluation using enzymatic and non-enzymatic assays, showed excellent potential of C. caesia EOs as compared to standard drugs. Specifically, in the enzymatic assay, leaf EO of C. caesia was resulted into the reduction of ROS and an increase in the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione S-transferase (GST) in OZ-stimulated PMNs. The EOs also displayed a remarkable antibacterial activity against Staphylococcus aureus , elucidating it as the most susceptible strain. Further, the in-silico prediction of the constituents was conducted using Swiss-ADME, and molecular docking analysis. Swiss-ADME revealed the drug-likeness and safety properties of constituents present in C. caesia EOs. The molecular docking study was carried out to interpret the possible interactions of phytoconstituents qualified in the Swiss-ADME study with two bacterial proteins (Tyrosyl-tRNA synthetase from Staphylococcus aureus (PDB ID: 1JIJ) and Glucosamine 6-phosphate synthase from Escherichia coli (PDB ID: 1XFF)), one fungal protein (N-myristoyl transferase from Candida albicans (PDB ID: 1IYL)) and one oxidative protein (Human peroxiredoxin 5 (PDB ID: 1HD2)). Furthermore, to validate the result of molecular docking, the biological activity of higher affinity constituents was also evaluated. As a result, the in vitro findings supported the in-silico prediction. Therefore, C. caesia or its constituents like curzerenone, camphor, eucalyptol, epicurzerenone, germacrone, viridifloral, muurola-4,10(14)-dien-1-ol, and globulol might be a valuable source for developing antioxidant and antimicrobial drugs. To the best of present author's knowledge, this is the first scientific report on the in-silico prediction of C. caesia constituents against bacterial, fungal and oxidative proteins through molecular docking, which may contribute to the development of various alternatives against multi-drug resistance. [Display omitted] • The chemical characterization of C. caesia EOs were evaluated through GC-MS. • Constituent-protein interactions were predicted using molecular docking. • The in-silico prediction was confirmed by in vitro validation of the constituents. • Leaf EO reduced ROS and enhanced SOD, CAT, and GST activity in OZ-stimulated PMNs. • The leaf EO could be utilized as an alternative to the reference standard (BHT). [ABSTRACT FROM AUTHOR]