Design of xanthorrhizol derivatives using in silico fragment-based drug design (FBDD) approach as lipoxygenase inhibitors

PURPOSE: Xanthorrhizol (XNT), a natural product isolated from Curcuma xanthorrhiza is known for its anti-inflammatory properties, through inhibition of pro-inflammatory enzymes, such as cyclooxygenase (COX) and inducible nitric oxide synthase (iNOS). Due to its small molecular weight (MW=281.33 g/mol) and biological activity, XNT is a suitable candidate to be further optimized as a more potent anti-inflammatory agent. Preliminary in vitro inhibitory studies showed that XNT exhibited mild activity (50.01% inhibition at concentration 100 µg/mL) against lipoxygenase (sLOX), an enzyme responsible for the eicosanoids biosynthesis pathway to form leukotrienes, that can induce inflammatory response towards human body. Hence, we aimed to improve the activity of XNT towards sLOX by modifying its hydroxyl functionality using combination of in silico methods, which are molecular docking and fragment-based drug design (FBDD) approach. In this study, a total of 1887 new XNT derivatives were generated as sLOX inhibitors by using LigBuilder software. Then, only the top 50 derivatives which exhibit binding energies, ranging from -8.4 to -9.0 kcal/mol were screened to remove duplicates. The number of derivates were further narrowed based on its ADME and druglikeness properties. Five promising XNT derivatives were chosen, consisting of different long alkyl chain with different heteroatoms, as potential Hyal inhibitors to be synthesized in the future. This work provided a more efficient approach for drug modification to produce more potent novel compounds using computational methods

Synthesis, Characterization, Antimicrobial activity and ADMET Analysis of S-benzyl-α-N-(anisoyl)-dithiocarbazate and its metal complexes

Dithiocarbazate derivatives have shown significant bioactivities especially as antibacterial agents. However due to the poor penetration into bacteria and its toxicity, their potential as a good antibacterial agent was dismissed. Therefore, the purpose of this study was to synthesize a new substituted dithiocarbazate derivative, S-benzyl-α-N-(anisoyl) dithiocarbazate (SB4OME) and its metal complex. SB4OME behaves as a tridentate chelating agent that coordinates with the metal ions with the general formula of [M(SB4OME)2] where M is Cu2+, Zn2+, Co2+ and Ni2+. All the compounds were characterized with various physico-chemical techniques including melting point analysis, FT-IR spectroscopy, UV–Vis spectroscopy, NMR spectroscopy, magnetic susceptibility and molar conductivity measurements. The antibacterial activity of all the compounds was tested against Staphylococcus aureus (ATCC 25923), Bacillus cereus (ATCC 11778), Pseudomonas aeruginosa (ATCC 27853) and Escherichia coli (ATCC 25922). The complexes significantly exhibited a stronger antibacterial activity than SB4OME against specific bacteria. All compounds showed a good drug like character through ADMET investigation, which was determined using SwissADME and Pro Tox-II. This showed that SB4OME and its complexes reduced the toxicity of dithiocarbazate derivatives and significantly enhanced their penetration in bacteria due to the coordination with metal ions resulting in increased bioactivity

Molecular docking and adme profiling of xanthorrhizol derivatives as hyaluronidase inhibitors

Hyaluronidase (Hyal) enzyme is one of the potential biological targets for the development of anti-inflammatory agents. Xanthorrhizol, a bisabolene sesquiterpenoid isolated from Curcuma xanthorrhiza has been reported showing anti-inflammatory activities against cyclooxygenase (COX), inducible nitric oxide synthase (iNOS), and interleukins (IL). However, the activity of xanthorrhizol as a Hyal inhibitor has not been exploited. In this study, a total of 26 xanthorrhizol derivatives having structural modifications at R1 - R4 scaffold were chosen. The molecular docking was performed to virtually screened their SAR activities towards Hyal while the ADME prediction was done to predict their pharmacokinetic profile. All derivatives bind to the active site of Hyal1 with binding energies ranging from -5.7 kcal/mol to -8.5 kcal/mol. Derivatives 24, and 14 having benzyloxy moiety at R1 position and polar moieties at R3 and R4 position showed lower binding energies (-8.3, and -7.9 kcal/mol, respectively) compared to apigenin, 28 and xanthorrhizol, 1. These derivatives also fulfilled all ADME and drug-likeness properties suggesting them as potential Hyal inhibitors. Through this work, the activity of xanthorrhizol derivatives against Hyal1 can be predicted and screened as a basis for future modifications of xanthorrhizol as potential Hyal inhibitor

Ethyl 1-(2-hy­droxy­eth­yl)-2-[2-(methyl­sulfan­yl)eth­yl]-1H-benzimidazole-5-carboxyl­ate

In the crystal structure of the title compound, C15H20N2O3S, the hy­droxy group is involved in the formation of O—H⋯N hydrogen bonds, which link two mol­ecules into a centrosymmetric dimer. Weak C—H⋯O hydrogen bonds further link these dimers into chains propagating along the a axis. The crystal packing exhibits π–π inter­actions between the five- and six-membered rings of neighbouring mol­ecules [centroid–centroid distance = 3.819 (2) Å] and short inter­molecular S⋯S contacts of 3.495 (1) Å

Ethyl 1-(2-hy­droxy­eth­yl)-2-propyl-1H-benzimidazole-5-carboxyl­ate

In the title compound, C15H20N2O3, the benzimidazole ring is essentially planar, with a maximum deviation from the mean plane of 0.012 (1) Å. The crystal structure is stabilized by inter­molecular O—H⋯N hydrogen bonds, forming centrosymmetric dimers, which are connected in the [100] direction through weak C—H⋯O contacts

Ethyl 1-(2-hy­droxy­eth­yl)-2-phenyl-1H-benzimidazole-5-carboxyl­ate

There are two mol­ecules in the asymmetric unit of the title compound, C18H18N2O3. In each one, the benzimidazole ring system is essentially planar, with maximum deviations of 0.027 (1) and 0.032 (1)Å, and makes dihedral angles of 38.64 (6) and 41.48 (6)°, respectively, with the attached benzene rings. An intra­molecular C—H⋯O hydrogen bond is observed in each mol­ecule. The two independent mol­ecules are connected into a dimer by two inter­molecular O—H⋯N hydrogen bonds. In the crystal, mol­ecules form a two-dimensional layers parallel to (012) via weak inter­molecular C—H⋯O hydrogen bonds. In addition, weak π-π stacking inter­actions are observed with centroid–centroid distances of 3.5244 (12) and 3.6189 (12) Å

Rheological Assessments on Alginate and Carrageenan as Nanoparticle Carriers for Topical Oral Cancer Drug

Commercially available topical oral drugs in current markets have low efficacy in delivery active load to the infected site due to poor formulation. Delivery of the active ingredients proven to be challenging as compared to skin due the presence of saliva and low shear. The aim of this project to improve formulation and characterised suitable hydrogels which later will be incorporated with nanoparticle drug for oral cancer. The gels are formulated at different pH values (4, 7, 10) and concentrations as such (0.1%, 0.15%, 0.2%, 0.25%, 0.5% and 1.0% for alginate whereas kappa-carrageenan and iota-carrageenan were formulated with 0.25%, 0.5% and 1.0%). The viscosity and zeta potential of the formulated gels are studied using HAAKE™ MARS™ rheometer and Zetasiser Nano-Z respectively. Findings revealed both 1% of kappa-carrageenan and 1% iota-carrageenan of pH 4 and pH 7 are the best candidates for nanoparticle drug delivery as the viscosity and zeta potential for 1% kappa-carrageenan (pH 4), 1% kappa-carrageenan (pH 7), 1% iota-carrageenan (pH 4), and 1% iota-carrageenan (pH 7) amongst the highest as such 70.507±6.190, 61.040±3.199, 59.490±7.799, 67.953±2.034 Pa·s, correspondingly with zeta potential value of -19.4 mV, -20.6 mV, -33.1 mV and -30.4 mV. All hydrogels formulated with different concentration were affected by pH values, by having pH value 4 and 7 appeared to have high viscosity with pseudoplastic behaviour based on the rheological profile, except for alginate due to high density sodium alginate was used in this study

Molecular docking and ADME profiles of β-Carboline analogues as potential antibiotic agents targeting DNA gyrase

Antibiotic resistance remains a major threat to humans worldwide, owing to the ability of bacteria and fungi to mutate over time, as well as a dramatic decline in the antibiotic pipeline. Plants are widely recognised as sources for various bioactive secondary metabolites that can be developed as a hit compound for further antibiotic discoveries. β-Carboline has been recognised as one of the hit compounds exhibiting various biological activities including antibacterial properties. However, the optimisation and development of the hit compound always hampered by long and expensive procedures. The in-silico approaches involving molecular docking and ADME profiling can be expedite the process. Herein, an in-house library of β-carboline and its 19 analogues were virtually screened to evaluate their antibiotic activities and drug-likeness properties using molecular docking and ADME profiling respectively. Docking studies showed that all 19 β-carboline analogues strongly bound to the target protein (-6.8 to -9.4 kcal/mol) except 1o (-6.7 kcal/mol), which exhibited binding energy comparable to the reference drug, novobiocin (-6.8 kcal/mol). Of these, derivatives 1l bound the strongest (-9.4 kcal/mol) mainly due to the hydrogen bond interactions that occurred between the carboxylic acid moiety with Val71. ADME profiling showed that all β-carboline analogues demonstrated favourable drug-likeness properties and obey the Lipinski Rule of 5 (Ro5). The analogues 1l showed only one inhibition on CYP2D6 suggesting less toxicity properties. Thus, through this work, the derivatives of β-carboline, especially 1l, may serve as hit compound for future development of finding effective antibiotic agent