SAR Analysis Research Articles

Antistaphylococcal Triazole-Based Molecular Hybrids: Design, Synthesis and Activity

Background: In the era of resistance, the design and search for new “small” molecules with a narrow spectrum of activity that target a protein or enzyme specific to a certain bacterium with high selectivity and minimal side effects remains an urgent problem of medicinal chemistry. In this regard, we developed and successfully implemented a strategy for the search for new hybrid molecules, namely, the not broadly known [2-(3-R-1H-[1,2,4]-triazol-5-yl)phenyl]amines. They can act as “building blocks” and allow for the introduction of certain structural motifs into the desired final products in order to enhance the antistaphylococcal effect. Methods: The “one-pot” synthesis of the latter is based on the conversion of substituted 4-hydrazinoquinazolines or substituted 2-aminobenzonitriles and carboxylic acid derivatives to the target products. The possible molecular mechanism of the synthesized compounds (DNA gyrase inhibitors) was investigated and discussed using molecular docking, and their further study for antistaphylococcal activity was substantiated. Results: A significant part of the obtained compounds showed high antibacterial activity against Staphylococcus aureus (MIC: 10.1–62.4 µM) and 5-bromo-2-(3-(furan-3-yl)-1H-1,2,4-triazol-5-yl)aniline and 5-fluoro-2-(3-(thiophen-3-yl)-1H-1,2,4-triazol-5-yl)aniline, with MICs of 5.2 and 6.1 µM, respectively, approaching the strength of the effect of the reference drug, “Ciprofloxacin” (MIC: 4.7 µM). The conducted SAR and ADME analyses confirm the prospects of the further structural modification of these compounds. The obtained [2-(3-R-1H-[1,2,4]-triazol-5-yl)phenyl]amines reveal significant antimicrobial activity and deserve further structural modification and detailed study as effective antistaphylococcal agents. The SAR analysis revealed that the presence of a cycloalkyl or electron-rich heterocyclic fragment in the third position of the triazole ring was essential for the antibacterial activity of the obtained compounds. At the same time, the introduction of a methyl group into the aniline moiety led to an enhancement of activity. The introduction of halogen into the aniline fragment has an ambiguous effect on the level of antistaphylococcal activity and depends on the nature of the substituent in the third position. Conclusions: Obtained [2-(3-R-1H-[1,2,4]-triazol-5-yl)phenyl]amines reveal significant antistaphylococcal activity and deserve for further detailed study as effective antibacterial agents.

Efficient synthesis of promising antidiabetic triazinoindole analogues via a solvent-free method: investigating the reaction of 1,3-diketones and 2,5-dihydro-3H-[1,2,4]triazino[5,6-b]indole-3-thione.

Diabetes poses a significant global health challenge, driving the search for effective management strategies. In the past years, α-amylase inhibitors have emerged as promising candidates for regulating blood sugar levels. In this concern, we have synthesized a series of novel 3-methyl-2-aroylthiazolo[3',2':2,3][1,2,4]triazino[5,6-b]indole derivatives via the regioselective reaction of 2,5-dihydro-3H-[1,2,4]triazino[5,6-b]indole-3-thione and 1,3-diketones in the presence of NBS under solvent-free conditions. Subsequently, the inhibitory potential of the newly synthesized 3-methyl-2-aroylthiazolo[3',2':2,3][1,2,4]triazino[5,6-b]indole derivatives was assessed against the α-amylase enzyme to probe their antidiabetic properties. In vitro studies revealed moderate to excellent α-amylase inhibitory activity, with IC50 values ranging from 16.14 ± 0.41 to 27.69 ± 0.58 μg ml-1. Furthermore, SAR analysis showed that compounds containing halogen groups exhibited superior inhibition potential, surpassing the standard drug Acarbose (IC50 = 18.64 ± 0.42 μg ml-1), particularly derivatives substituted with 4-fluoro and 2,4-dichloro groups, with IC50 values of 16.14 ± 0.41 μg ml-1 and 17.21 ± 0.15 μg ml-1, respectively. Additionally, molecular docking unveiled the binding modes of ligands with the active site of A. oryzae α-amylase. Encouragingly, the theoretical analyses closely mirrored the experimental findings, further underlining the promise of these synthetic molecules as potent α-amylase inhibitors.

Synthesis, Biological Screening, and Molecular Docking of Hybrid Pyrazole Scaffolds for Antitubercular and Antimicrobial Activity

AbstractThis study reports the synthesis, characterization, and docking analysis of 21 novel compounds, including asymmetric dihydropyridines (4a–4o) and chalcones (6a–6f), derived from coupling 1,3‐(substituted)‐diphenyl‐1H‐pyrazole‐4‐carbaldehyde with active methylene compounds and 3‐acetyl‐4‐hydroxycoumarin, respectively. Structural confirmation was achieved through 1H and 13C NMR, IR, and mass spectrometry. Biological screening against mycobacterium tuberculosis H37Ra identified compounds 4b, 4d, 4f, 4g , 4i, 4k, 6e, and 6f as significant antitubercular agents. Antibacterial evaluation at 30 µg/mL showed selective inhibition of gram‐positive bacteria, with compound 6e active against Staphylococcus aureus and Bacillus subtilis, and 6f showing activity specifically against S. aureus. Docking studies indicated effective InhA binding (ΔG = −3.52 to −7.27 kcal/mol) and inhibition constants ranging from 2640 to 4.71 µM. Key binding interactions with residues TYR156 and ILE192 were observed, enhancing affinity, particularly for compound 6e. The SAR analysis emphasized the enhanced antitubercular potency of 2‐chloroacetyl and 2,4‐dichlorobenzoyl substitutions in the dihydropyridine series, while in the chalcone series, specific substitutions, such as the 3‐nitro substitution in 6e, enhance antitubercular and antimicrobial potency due to stronger hydrogen bonding and increased polar surface area, while the 4‐fluoro substitution in 6f confers selective activity against S. aureus.

A circular-shaped two-slot foam-based flexible UWB antenna for medical applications

The biomedical industries have recently shown a great deal of interest in the study of flexible wireless devices. Wearable antennas are vital in medical applications as they enable continuous, real-time monitoring of patient health. In this context, a circular-shaped two-slot flexible ultra-wideband microstrip antenna is presented for use in the medical field. An inexpensive, lightweight flexible foam substrate material of 2 mm thickness with dielectric constant 1.07 and copper foil of 50 microns for patch is proposed in the fabrication of antenna. This paper presents a circularly shaped antenna of size 48×36mm2 with patch radius of 12 mm and detailed analysis of bending, on-body and SAR with actual measurement. A good matching is observed between measured and simulated results with the bandwidth of 10 GHz over the ultra-wideband operating frequencies of 3.1–10.7 GHz. The slot and stub added into geometry has resulted into the total gain of 4.7 dB, with good impedance matching. An extensive SAR analysis for 1 and 10 g tissue has been carried out with average SAR of 0.0215 W/kg and 0.0138 W/kg respectively and found below the safety limit as prescribed by IEEE.

Safety assessment of the substance 2,2'-oxydiethylamine for use in plastic food contact materials.

The EFSA Panel on Food Contact Materials assessed the safety of 2,2'-oxydiethylamine, which is intended to be used at up to 14% w/w as a monomer along with adipic acid and caprolactam to make polyamide thin films intended for single use, in contact with all types of food under all conditions of time and temperature. Specific migration of 2,2'-oxydiethylamine was tested from a polyamide film in water and was below the limit of quantification (LOQ) of 0.015 mg/kg. Migration of impurities has been estimated pro-rata. Migrating oligomers were identified and semi-quantified in 10% ethanol, 3% acetic acid and olive oil. Considering the measured migration and the virtual presence at the LOQ of the oligomers below 1000 Da containing the substance, the estimated migration of these oligomers would be 1.042 mg/kg. Genotoxicity studies were performed on the substance and on 1-oxa-4,11,18-triazacycloeicosane-5,10,17-trione and 1-oxa-4,11,18,25-tetraazacycloheptacosane-5,10,17,24-tetraone. (Q)SAR analyses were provided on the oligomers of higher molecular masses. Based on these data, the Panel excluded genotoxicity concerns for the substance and its oligomers. From a 90-day toxicity study on the 1-oxa-4,11,18-triazacycloeicosane-5,10,17-trione, the Panel identified a NOAEL of 1040 mg/kg bw per day. Based on their physico-chemical properties and experimental data, the Panel considered the potential for accumulation in humans of the oligomers containing the substance of no concern. The Panel concluded that the substance is not of safety concern for the consumer if it is used as a comonomer with 99.6% minimum purity at up to 14% w/w to manufacture polyamide films (maximum thickness: 25 μm) and intended to be used in contact with all types of foods, except infant formula and human milk, at all time and temperature conditions. The migrations of the substance and of the oligomers below 1000 Da containing the substance should not exceed 0.05 and 5 mg/kg food, respectively.

Classification models and SAR analysis of anaplastic lymphoma kinase (ALK) inhibitors using machine learning algorithms with two data division methods.

Anaplastic lymphoma kinase (ALK) plays a critical role in the development of various cancers. In this study, the dataset of 1810 collected inhibitors were divided into a training set and a test set by the self-organizing map (SOM) and random method, respectively. We developed 32 classification models using Support Vector Machines (SVM), Decision Trees (DT), Random Forests (RF), and Extreme Gradient Boosting (XGBoost) to distinguish between highly and weakly active ALK inhibitors, with the inhibitors represented by MACCS and ECFP4 fingerprints. Model 7D which was built by the RF algorithm using training set 1/test set 1 divided by the SOM method, provided the best performance with a prediction accuracy of 90.97% and a Matthews correlation coefficient (MCC) value of 0.79 on the test set. We clustered the 1810 inhibitors into 10 subsets by K-Means algorithm to find out the structural characteristics of highly active ALK inhibitors. The main scaffolds of highly active ALK inhibitors were also analyzed based on ECFP4 fingerprints. It was found that some substructures have a significant effect on high activity, such as 2,4-diarylaminopyrimidine analogues, pyrrolo[2,1-f][1,2,4]triazin, indolo[2,3-b]quinoline-11-one, benzo[d]imidazol and pyrrolo[2,3-b]pyridine. In addition, the subsets were summarized into several clusters, among which four clusters showed a significant relationship with ALK inhibitory activity. Finally, Shapley additive explanations (SHAP) was also used to explain the influence of modeling features on model prediction results. The SHAP results indicated that our models can well reflect the structural features of ALK inhibitors.

Novel 4-((3-fluorobenzyl)oxy)benzohydrazide derivatives as promising anti-prostate cancer agents: Synthesis, characterization and in vitro & in silico biological activity studies

In this study, ten novel halogenated arylidenehydrazide derivatives were synthesized and characterized through ¹H, ¹³C APT, ¹⁹F NMR, HSQC, HMBC, HRMS, and FT-IR techniques. Cytotoxic evaluations against PC3 prostate cancer and HUVEC cell lines identified compounds 8 and 14 as lead candidates, achieving IC₅₀ values of 4.49 µM and 4.78 µM, respectively, with notable selectivity indexes of 12.15 and 11.78, underscoring their specificity against PC3 cells. Molecular docking studies targeting AR, VEGFR1, EGFR, and VEGFR2 suggested potential inhibitory mechanisms, with compounds 8 and 14 displaying substantial binding affinities for AR and VEGFR1. Compound 8 achieved IFD scores of -12.900 kcal/mol for AR and -10.895 kcal/mol for VEGFR1, while compound 14 recorded scores of -10.323 kcal/mol and -10.379 kcal/mol, respectively. Complementary MM-GBSA analyses revealed favorable binding energies, with compound 8 yielding ΔG values of -76.60 kcal/mol (AR) and -78.08 kcal/mol (VEGFR1) and compound 14 showing -80.67 kcal/mol (AR) and -78.61 kcal/mol (VEGFR1). MD simulations confirmed complex stability over 50 ns, indicating that compound 14 exhibited enhanced binding stability with key residues in AR and VEGFR1. ADME predictions highlighted drug-like properties, particularly for compounds 8 and 14, with high lipophilicity and favorable absorption characteristics, despite low aqueous solubility. SAR analysis emphasized the beneficial impact of halogen substitutions on potency and selectivity, establishing compounds 8 and 14 as promising candidates for further therapeutic development.

Novel pyrrole based triazole moiety as therapeutic hybrid: synthesis, characterization and anti-Alzheimer potential with molecular mechanism of protein ligand profile

As a springboard to explore novel potent inhibitors of cholinesterase enzymes (AChE and BChE) responsible for causing Alzheimer disorder, the current study was conducted to synthesize pyrrole derived triazole based Schiff base scaffolds by facile synthetic route. These compounds were validated by 1HNMR, 13CNMR and HREI-MS. All these scaffolds (1–16) were examined for their inhibitory activity against AChE and BChE in contrast to Donepezil (10.20 ± 0.10 and 10.80 ± 0.20 µM) and Allanzanthone (12.40 ± 0.10 and 13.10 ± 0.10 µM). All pyrrole derived triazole based Schiff base scaffolds (1–16) showed varied range of inhibitory potentials against acetylcholinesterase and butyrylcholinesterase enzymes with lowest inhibition concentration values ranging from 5.10 ± 0.40–27.10 ± 0.10 µM (for AChE) and 5.60 ± 0.30–28.40 ± 0.30 µM (for BChE). SAR analysis of these derivatives revealed analog 7 as lead molecule against targeted enzyme, while analog 6 and 11 were ranked as second and third most potent scaffolds. Binding affinity and selectivity of potent molecules against targeted enzymes were examined by molecular docking and obtained results showed that potent molecule have versatile significant binding interactions with stated enzymes. Furthermore, safety profiles of potent analogues were predicted via ADMET protocols.Graphical

Neuroprotective Effect of Natural Indole and β-carboline Alkaloids against Parkinson's Disease: An Overview.

Parkinson's disease (PD) is a devastating neurodegenerative condition that mostly damages dopaminergic neurons in the substantia nigra and impairs human motor function. Males are more likely than females to have PD. There are two main pathways associated with PD: one involves the misfolding of α-synuclein, which causes neurodegeneration, and the other is the catalytic oxidation of dopamine via MAO-B, which produces hydrogen peroxide that can cause mitochondrial damage. Parkin (PRKN), α-synuclein (SNCA), heat shock protein (HSP), and leucine-rich repeat kinase-2 (LRRK2) are some of the target areas for genetic alterations that cause neurodegeneration in Parkinson's disease (PD). Under the impact of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is also important in Parkinson's disease (PD), inhibition of mitochondrial complex 1 results in enhanced ROS generation in neuronal cells. Natural products are still a superior option in the age of synthetic pharmaceuticals because of their lower toxicity and moderate side effects. A promising treatment for PD has been discovered using beta-carboline (also known as " β-carboline") and indole alkaloids. However, there are not many studies done on this particular topic. In the herbs containing β-carbolines and indoles, the secondary metabolites and alkaloids, β-carbolines and indoles, have shown neuroprotective and cognitive-enhancing properties. In this review, we have presented results from 18 years of research on the effects of indole and β-carboline alkaloids against oxidative stress and MAO inhibition, two key targets in PD. In the SAR analysis, the activity has been correlated with their unique structural characteristics. This study will undoubtedly aid researchers in looking for new PD treatment options.

A Comprehensive Analysis on Galantamine Based Hybrids for the Management of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive chronic age-related neurodegenerative brain disorder characterized by the loss of memory and other cognitive functions. The exact etiology of AD is still under investigation, however several factors such as low level of neurotransmitter acetylcholine (ACh), aggregation of amyloid beta (Aβ) in the form of Aβ plaques, hyperphosphorylation of tau protein into neurofibrillary tangles (NFTs), oxidative stress, and metal ion imbalance are the major hallmarks of this disease. Of the multiple hypotheses for AD, the amyloid-β (Aβ) and cholinergic hypothesis are the main targeting hypotheses for AD. Some researchers hypothesized that the primary event associated with the cholinergic neurotransmitter (acetylcholine) is memory loss and cognitive impairment. Due to the disease's complicated pathogenesis, long-term therapy with a single target candidate is futile. As a result, multitargeted and multifunctional therapies have emerged. Various research teams are concentrating on addressing multiple disease factors through hybridization techniques. Consequently, this hybridization approach has been applied to all core scaffolds, including galantamine. In this article, we tried to provide a thorough overview of the most recent developments on galantamine, a prospective AChE inhibitor, and its hybrid analogs as possible therapeutic agents for treating AD. Furthermore, we also provided the design, synthesis, and SAR analysis of the galantamine-based compounds used in the last decades for the management of AD.

Multi-functional tyrosinase inhibitors derived from kojic acid and hydroquinone-like diphenols for treatment of hyperpigmentation: Synthesis and in vitro biological evaluation.

A series of multi-functional tyrosinase inhibitors derived from kojic acid (KA) and hydroquinone-like diphenols were designed and synthesized using click chemistry. The in vitro enzymatic assay revealed that all compounds containing a free enolic structure showed excellent activity against tyrosinase (IC50 = 0.14-3.7 µM), being significantly more potent than KA. The most active compounds were catechol (6c) and α-naphthol (6i) analogs with 138- and 96-fold higher potency than KA. On the other hand, all free phenolic compounds (6a-c and 6g-j) derived from aromatic diols showed outstanding free radical scavenging activities superior to KA. Certainly, the α-naphthol derivative 6i with IC50 = 10.1 µM was the most active anti-oxidant, being as potent as quercetin. The SAR analysis indicated that the enolic head of the conjugate molecules mainly contributes to the anti-tyrosinase activity, and the free phenolic part of the molecules can offer anti-oxidant potency. The anti-melanogenic assay of the most promising derivative, 6i, against melanoma (B16F10) cells demonstrated that the prototype compound 6i can significantly reduce the melanin content, more effectively than KA. By using a conjugation strategy, we have improved the tyrosinase inhibitory and radical scavenging activity in the multi-functional agents such as 6i over the parent compound KA, being potentially useful in the treatment of hyperpigmentation and other skin disorders.

Pharmacophore-based SAR Analysis and Synthetic Route Review of Imidazole Core Analogues

Pharmacophore-based SAR Analysis and Synthetic Route Review of Imidazole Core Analogues

Recent Advances in Medicinal Chemistry of Memantine Against Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic progressive, age-related neurodegenerative brain disorder characterized by the irreversible decline of memory and other cognitive functions. It is one of the major health threat of the 21st century, which affects around 60% of the population over the age of 60 years. The problem of this disease is even more major because the existing pharmacotherapies only provide symptomatic relief without addressing the basic factors of the disease. It is characterized by the extracellular deposition of amyloid β (Aβ) to form senile plaques, and the intracellular hyperphosphorylation of tau to form neurofibrillary tangles (NFTs). Due to the complex pathophysiology of this disease, various hypotheseshave been proposed, including the cholinergic, Aβ, tau, oxidative stress, and the metal-ion hypothesis. Among these, the cholinergic and Aβ hypotheses are the primary targets for addressing AD. Therefore, continuous advances have been made in developing potential cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists to delay disease progression and restore cholinergic neurotransmission. In this review article, we tried to comprehensively summarize the recent advancement in NMDA receptor antagonist (memantine) and their hybrid analogs as potential disease-modifying agents for the treatment of AD. Furthermore, we also depicted the design, rationale, and SAR analysis of the memantine-based hybrids used in the last decade for the treatment of AD.

Design, synthesis, in vitro and in silico studies of novel piperidine derived thiosemicarbazones as inhibitors of dihydrofolate reductase.

Dihydrofolate reductase (DHFR), an essential enzyme in folate metabolism, presents a promising target for drug development against various diseases, including cancer and tuberculosis. Herein, we present an integrated approach combining in vitro biochemical assays with in silico molecular docking analysis to evaluate the inhibitory potential of 4-piperidine-based thiosemicarbazones 5(a-s) against DHFR. In our in vitro study, a novel series of 4-piperidine-based thiosemicarbazones 5(a-s) were assessed for their inhibitory activity against DHFR enzyme. The synthesized compounds 5(a-s) exhibited potent inhibition with IC50 values in the range of 13.70 ± 0.25 µM to 47.30 ± 0.86 µM. Among all the derivatives 5p displayed highest inhibitory activity. Simultaneously, in silico analysis were performed and compared with standard drug (Methotrexate) to predict the binding affinity and interaction pattern of synthesized compounds with DHFR active site. SAR analysis was done to elucidate how structural modifications impact compound's biological activity, guiding the rational design of potent and selective drug candidates for targeted diseases. These findings may provide a comprehensive assessment of 4-piperdine-based thiosemicarbazones as DHFR inhibitors and contribute to the development of novel therapeutics targeting DHFR-associated diseases.

Design, synthesis, and evaluation of chalcone derivatives as xanthine oxidase inhibitors

Xanthine oxidase (XO) is an important enzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid in the catabolism of purines in humans. This makes XO a well-recognized target in alleviating hyperuricemia. The present study adapted a structure-based drug discovery approach to develop potent and low-toxicity XO inhibitors with the chalcone skeleton. We introduced a carboxyl group and a hydroxyl group to the B ring and modified the A ring. 35 chalcone derivatives were designed and synthesized. All the 35 derivatives exhibited higher XO inhibition activities (IC50 = 0.064–0.559 μM) compared with allopurinol (IC50 = 2.588 μM). Their high affinity was attributed to strong hydrogen bond interactions formed between the introduced carboxyl and hydroxyl groups with key amino acid residues in XO. SAR analysis disclosed that carboxyl, hydroxyl, ethyl (12c), methylamino (12h), dimethylamino (12i), indolin (13k), and indol (13l) groups played important roles in improving the whole molecules’ inhibition potency against XO. ADME predictions and cytotoxicity assays suggested their pharmacokinetic characteristics and biocompatibility were desirable. Additionally, 12c exhibited a significant hypouricemic effect on potassium oxonate-induced hyperuricemia rats after orally administrated at a dose range of 10–40 mg/kg, representing a promising anti-hyperuricemia potential for further optimization and development.

Rational Design and Synthesis of Novel Benzimidazole Derivatives as Potential β-Glucosidase Inhibitors

Background: β-Glucosidase has a variety of biological functions. A structural model for a potential β-glucosidase inhibitor has been proposed in the previous studies. Objective: A series f new diaryl derivatives linked through benzimidazole have been randomly and rationally designed, synthesized, and evaluated for their inhibitory activities against β-glucosidase (almond). The proposed structural model provides a new strategy for the design of potent β-glucosidase inhibitors. Methods: According to the model, a series of benzimidazole derivatives were designed and synthesized, and their inhibitory activity, Ki value, inhibitory type, and binding mode analysis (PDB ID: 2J7C) on β-glucosidase (almond) were evaluated. Results: Two compounds 7b and 7d were the best inhibitors with IC50 values of 7.86 M and 3.52 μM, respectively. Their Ki values were calculated to be 9.91 μM and 5.81 μM, respectively. Conclusion: The SAR analysis suggested that such benzimidazole derivatives might bind to the active site of β-glucosidase mainly through hydrogen bonds on o-trihydroxyphenol; the additional phenyl ring on the other side towards the solvent-exposed region played a very important role in improving their inhibitory activity against β-glucosidase

Novel pyrimidine-anthraquinone dyes: Design, synthesis, textile applications & their computational SAR analysis

The integration of functional textiles production approach, correlated with organic synthesis and computational elaboration of synthesized anthraquinone-based pyrimidine dyes, makes a significant contribution in multidisciplinary research. The central focus of this project is the production of multipurpose chemical moieties, addressing the current imperative to reduce the human consumption and mitigate the depletion of natural resources by employing cost-effective methods. The present study is focused to synthesize some new molecules as dyes having antibacterial and UV-protection ability. These synthesized dyes were characterized by UV, FT-IR, 1H NMR, 13C NMR spectroscopic analysis that confirmed the structures of targeted molecules. These targeted dyes were applied to fabric and their colorfastness properties were checked according to ISO recommended procedures. The fastness results supported efficient fixation and fading resistance. The Ultraviolet Protection Factor (UPF) studies were conducted to measure the UV-protection ability of the dyed fabric. Furthermore, antibacterial ability of dyes was also checked, and experimental results were compared through molecular docking study. Dyes were screened for their absorbance under solvents of different polarity, and these were further analyzed by TD-DFT and DFT analysis.

Discovery of membrane-targeting amphiphilic honokiol derivatives containing an oxazolethione moiety to combat methicillin-resistant Staphylococcus aureus (MRSA) infections

Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a major pathogen causing infections in hospitals and the community, and there is an urgent need for the development of novel antibacterials to combat MRSA infections. Herein, a series of amphiphilic honokiol derivatives containing an oxazolethione moiety were prepared and evaluated for their in vitro antibacterial and hemolytic activities. The screened optimal derivative, I3, exhibited potent in vitro antibacterial activity against S. aureus and clinical MRSA isolates with MIC values of 2–4 μg/mL, which was superior to vancomycin in terms of its rapid bactericidal properties and was less susceptible to the development of resistance. The SARs analysis indicated that amphiphilic honokiol derivatives with fluorine substituents had better antibacterial activity than those with chlorine and bromine substituents. In vitro and in vivo toxicity studies revealed that I3 has relatively low toxicity. In a MRSA-infected mouse skin abscess model, I3 (5 mg/kg) effectively killed MRSA at the infected site and attenuated the inflammation effects, comparable to vancomycin. In a MRSA-infected mouse sepsis model, I3 (12 mg/kg) was found to significantly reduce the bacterial load in infected mice and increase survival of infected mice. Mechanistic studies indicated that I3 has membrane targeting properties and can interact with phosphatidylglycerol (PG) and cardiolipin (CL) of MRSA cell membranes, thereby disrupting MRSA cell membranes, further inducing the increase of reactive oxygen species (ROS), protein and DNA leakage to achieve rapid bactericidal effects. Finally, we hope that I3 is a potential candidate molecule for the development of antibiotics to conquer superbacteria-related infections.

Design, synthesis, and in vitro and in silico study of 1-benzyl-indole hybrid thiosemicarbazones as competitive tyrosinase inhibitors.

Developing new anti-tyrosinase drugs seems crucial for the medical and industrial fields since irregular melanin synthesis is linked to the resurgence of several skin conditions, including melanoma, and the browning of fruits and vegetables. A novel series of N-1 and C-3 substituted indole-based thiosemicarbazones 5(a-r) are synthesized and further analyzed for their inhibition potential against tyrosinase enzyme through in vitro assays. The synthesized compounds displayed very good to moderate inhibition with half maximal inhibitory concentration in the range of 12.40 ± 0.26 μM to 47.24 ± 1.27 μM. Among all the derivatives 5k displayed the highest inhibitory activity. According to SAR analysis, the derivatives with 4-substitution at the benzyl or phenyl ring of the thiosemicarbazones exhibited better inhibitory potential against tyrosinase. In silico analysis (including ADMET prediction and molecular docking) was conducted and compared with the standard drug (kojic acid). These findings may help the hunt for new melanogenesis inhibitors that the food and cosmetics industries may find valuable.

Design and Assessment of Fighter Pilot Assistance Systems for Air-to-Air Refuelling with Probe-and-Drogue-Equipment

Air-to-air refuelling (AAR) with a probe-and-drogue system is a highly demanding process for fighter pilots. In the frame of the project “Future Air-to-Air Refuelling” (F(AI)2R) the German Aerospace Center (DLR) is designing concepts for assistance systems to support fighter pilots during this manoeuvre. The AAR process was examined using a hierarchical task analysis (HTA) based on a literature review and semi-structured interviews with Eurofighter-, Tornado- and test pilots. “Situation Awareness Requirements” (SAR), which represent relevant parameters for the situation awareness of the fighter pilot were derived from the HTA and rated by pilots according to their relevance. The collected data was then used to design different concepts of pilot assistance systems using a morphological box and a decision matrix. The concepts were visualised as storyboards, assessed by test pilots of the “Wehrtechnische Dienststelle 61” (WTD 61) and optimized based on their feedback. In this paper, the used methodology as well as the results of the HTA and SAR analysis are presented. Besides that, storyboards for pilot assistance systems displaying the overtake speed “German Patent No. 10.2022.110.505” and the “Contact Assistance, Status and Warning System” (CASWS) “German Patent No. 10.2022.123.653” are described. Additionally, the planned implementation using a HoloLens 2 is explained and the strategy for the subsequent simulator study on the DLR fighter aircraft simulator “Military AiR vehicle Simulator – Fast Integration Testbed” (MARS-FIT) is described.