Analog Design Research Articles

Design, synthesis and antifungal activity of arylhydrazine analogs containing diphenyl ether fragments.

Succinate dehydrogenase (SDH) represents a critical target in the development of novel fungicides. To address the growing issue of resistance and safeguard the economic viability of agricultural production, the pursuit of new succinate dehydrogenase inhibitors (SDHIs) has emerged as a significant focus of contemporary research. In this project, 32 arylhydrazine derivatives containing diphenyl ether structural units were synthesized and evaluated for their fungicidal activities against Rhizoctonia solani, Sclerotinia sclerotiorum, Alternaria alternata, Gibberella zeae, Alternaria solani and Colletotrichum gloeosporioides. In an in vitro fungicidal activity assay, compound D6 showed significant inhibitory activity against R. solani with a half-maximum effective concentration (EC50) of 0.09 mg L-1. The in vivo fungicidal activity demonstrated that compound D6 inhibited R. solani by 95.39% in rice leaves, which was significantly better than that of boscalid (85.76%). The results of SDH enzyme assay, molecular docking simulation, mitochondrial membrane potential assay, cytoplasmic release studies and morphological observations demonstrated that the target compound D6 not only had significant SDH inhibitory activity, but also affected the membrane integrity of mycelium. Bioactivity screening and validation of the mechanism of action indicated that compound D6 was a potentially unique SDHI, acting on SDH while also affecting cell membrane permeability, which deserved further study. © 2024 Society of Chemical Industry.

Theoretical study of ultrafast spin dynamics in a Co-Fe molecular Prussian blue analog and spin logic functionality design

Theoretical study of ultrafast spin dynamics in a Co-Fe molecular Prussian blue analog and spin logic functionality design

Optimization of Advanced Support Parameters of Surrounding Rock in Tunnels Constructed by ADECO-RS

So as to efficiently address the distortion of surrounding rock in tunnels constructed utilizing ADECO-RS, it is crucial to define suitable parameters for advanced support systems. This study took the 8 # tunnel in the F3 portion of the E60 Expressway in Georgia as an engineering case. Initially, the original support scheme underwent systematic monitoring and analysis in the field. Subsequently, the FLAC3D 6.0 software was employed to examine the influence of the advanced pipe roof and tunnel face fiberglass bolts on the steady state of the surrounding rock. Optimization of the support parameters was also proposed. Further, the sensitivity of different parameters to the distortion of the rock surrounding the tunnel was analyzed and ranked via an orthogonal experiment. Ultimately, the effectiveness of the optimization scheme was evaluated by numerical methods and field observations. The findings of the research indicate the following: (1) The monitoring results of the original support parameters show that the irrational design of the support parameters can bring about deformation non-convergence in the tunnel’s surrounding rock. Support parameters must be optimized. (2) The spacing of the pipe roof is positively correlated with the distortion of the surrounding rock. In contrast, the length and the grouting strength are negatively correlated with the distortion of the surrounding rock. The reinforcement density, length, and lap length of glass fiber bolts exhibit an inverse relationship with the distortion of the surrounding rock. (3) The efficacy of pipe shed grouting in mitigating subsidence and deformation of the vault is superior, followed by the spacing of the supports. In contrast, the length of the supports demonstrates comparatively lesser effectiveness. Under optimal parameters, the vault subsidence was reduced by 23.2%, 10.2%, and 2.0%, respectively. The most significant factor controlling the extrusion deformation of the tunnel face is bolt lap length, followed by reinforcement density and then reinforcement length. Extrusion displacement was reduced by 52.5%, 40.3%, and 9.3%, respectively, under the optimal parameters. (4) In comparison to the primordial support system, the optimized support scheme reduces the subsidence of the vault by about one time and the convergence deformation around the cave by about two times. The research findings offer guidance for analogous engineering support design and parameter optimization.

Design and Synthesis of Mycophenolic Acid Analogues for Osteosarcoma Cancer Treatment

Design and Synthesis of Mycophenolic Acid Analogues for Osteosarcoma Cancer Treatment

Deep Analogical Generative Design and Evaluation: Integration of Stable Diffusion and LoRA

Abstract The rapid evolution of generative design through artificial intelligence has opened new avenues for innovative product styling. Integrating this efficient generative technology with established professional theories presents a novel challenge in contemporary international design research. In response to this challenge, this paper introduces a pioneering and collaborative approach for the swift generation of automobile styling designs. The primary objective is to investigate an intelligent generation method that incorporates analogical reasoning and Stable Diffusion to support industrial designers in innovating product styling. This study scrutinizes traditional analogical reasoning design alongside the intelligent analogical reasoning design proposed herein, elucidating the distinctions through multidimensional comparisons using illustrative examples. The proposed methodological framework encompasses several key steps. Initially, a dataset comprising branded automobile images is meticulously constructed. Subsequently, an exclusive style model is trained leveraging Stable Diffusion techniques, coupled with advanced computer graphics and machine learning methodologies. Following this, design requirements are inputted, facilitating intelligent analogical reasoning design across multiple spatial dimensions to yield diverse and innovative automobile styling solutions. Finally, eye-tracking experiments are conducted to quantitatively compare the traditional analogical reasoning design approach with the Stable Diffusion-based analogical reasoning design method. The results substantiate that the latter effectively generates innovative and diversified automobile design solutions. This research contributes to enhancing the quality of automobile styling design, optimizing the design efficiency of enterprises, and catalyzing innovation in the automobile styling design process.

Analysis of the dynamics of a complex, multipathway reaction: Insulin dimer dissociation.

The protein hormone insulin forms a homodimer that must dissociate to bind to its receptor. Understanding the kinetics and mechanism of dissociation is essential for rational design of therapeutic analogs. In addition to its physiological importance, this dissociation process serves as a paradigm for coupled (un)folding and (un)binding. Based on previous free energy simulations, insulin dissociation is thought to involve multiple pathways with comparable free energy barriers. Here, we analyze the mechanism of insulin dimer dissociation using a recently developed computational framework for estimating kinetic statistics from short-trajectory data. These statistics indicate that the likelihood of dissociation (the committor) closely tracks the decrease in the number of (native and nonnative) intermonomer contacts and the increase in the number of water contacts at the dimer interface; the transition state with equal likelihood of association and dissociation corresponds to an encounter complex with relatively few native contacts and many nonnative contacts. We identify four pathways out of the dimer state and quantify their contributions to the rate, as well as their exchange, by computing reactive fluxes. We show that both the pathways and their extents of exchange can be understood in terms of rotations around three axes of the dimer structure. Our results provide insights into the kinetics of insulin analogues and, more generally, how to characterize complex, multipathway processes.

Structure-property relationship of pea protein microgels as fat analogues in Pickering oil-in-water emulsions: effect of salt addition.

The design of plant-based microgels provides a platform for food ingredients to enhance palatability and functionality. This work aimed to explore the modifying effect of salt addition (KCl) on the structure of pea protein microgel particles (PPI MPs), on the interfacial adsorption and characteristics of formed emulsions as fat analogues. Salt addition (0-200 mmol L-1) promoted a structural transformation from α-helix to β-sheet, increased the surface hydrophobicity (from 1160.8 to 2280.7), and increased the contact angle (from 56.73° to 96.47°) of PPI MPs. The electrostatic shielding effect led to the tighter packing of MPs with irregular structures and lowered the adsorption energy barrier. Notably, salt-treated PPI MPs could adjust their adsorption state at the interface. The discernible adsorption of PPI MPs with 200 mmol L-1 salt addition that possessed enhanced anti-deformation ability dominated the interfacial stabilization, whereas a relatively rougher stretched continuous interfacial film formed after spreading and deformation of 0 mmol L-1 MPs. A tribological test suggested that emulsion stabilized by MPs at 0 (0.0053) and 80 mmol L-1 (0.0068) had similar friction coefficients to commercial mayonnaise (0.0058), whereas a higher salt concentration (200 mmol L-1) lowered its oral sensation due to the adsorption layer and enhanced the resistance to droplet coalescence during oral processing. Salt could be a modifier to tune the structure of microgels, and further promote the formation and attributes of emulsions. This study would improve application attributes of PPI MPs in the design of realistic fat analogues. © 2024 Society of Chemical Industry.

8410 Lipid modification enhances the calcemic and bone building effects of injected PTH(1-14) and PTH(1-11) fragment peptides in mice

Abstract Disclosure: J. Höppner: None. H. Noda: None. A. Khatri: None. H. Jüppner: None. T.J. Gardella: None. PTH analogs with improved actions in vivo are of interest as potential treatment options for bone and mineral ion diseases such as hypoparathyroidism and osteoporosis. The efficacies in vivo of conventional PTH peptides are generally limited by rapid rates of clearance from the circulation (t1/2 = ∼ 5-30 minutes) and relatively short-dwell times on the receptor (PTH1R). This is especially true for small fragment analogs, such as M (modified)-PTH(1-14), and M-PTH(1-11), which have only been shown to be active in vitro. We explored whether PTH fragment peptide efficacy in vivo could be enhanced by addition of a lipid chain (e.g., a C15 palmitoyl chain (palm)) to either the peptide C-terminus or to the side chain of the amino acid residue at position 11 or 13. The C-tail lipid modifications were specifically designed to promote binding to serum albumin, and hence extend circulation half-life, while the lipid chains at sidechains of residue positions 11 and 13 were designed, based on structural models, to anchor the ligand to the receptor in situ -- i.e. by projection of the acyl chain between two adjacent transmembrane helices and into the surrounding plasma membrane -- to thereby extend receptor dwell time. Assessment of cAMP signaling potencies in HEK293/hPTH1R/glosensor cells revealed that both types of lipid modifications can preserve agonist potency, and that the lipid extensions at position 11 or 13 can indeed prolong receptor dwell times, as shown by extended durations of cAMP signaling after initial binding of Palm 11 or 13-modified M-PTH(1-14) and M-PTH(1-11) peptide fragment. Single subcutaneous injection of either Palm-13-M-PTH(1-14) or Palm-11-M-PTH(1-11) into mice resulted in prolonged increases in blood serum calcium levels, while 14 days of daily injection resulted in profound increases in bone mass, as measured by uCT, and marked increases in blood levels of the bone turnover markers CTX1 and P1NP, whereas non-lipidated M-PTH(1-14) control peptides were inactive in vivo. Peptide lipidation thus holds promise as a strategy to employ in the design of new PTH analogs with improved efficacies in vivo. Presentation: 6/1/2024

Effect of Implant Analog Design and Additively Manufactured Casts' Printing Layer Thickness on the Linear and Angular Accuracy of Analogs for Direct Digital Workflow: An In Vitro Study.

To evaluate how implant analog design and printing layer thickness affect the linear and angular accuracy of implant analogs in additively manufactured casts, comparing with conventional implant analogs in stone casts. A reference cobalt chromium mandibular model with a single implant was digitized with an industrial optical scanner and scan bodies compatible with a pressure/friction fit (S) or a screw-retained (N) implant analog for direct digital workflow. These scans were used to fabricate casts with 50 μm (S-50 and N-50) and 100 μm (S-100 and N-100) layer thickness (n=10). Ten stone casts were made after single-step closed-tray polyvinylsiloxane impressions of the model (CNV). All casts were digitized with the same metal scan body and scanner used to digitize the master model, and these scans were superimposed over the scan of the master model to measure the linear (x, y, and z-axes) and angular (XY and YZ planes) deviations (Geomagic Control X). The precision of measured deviations was defined with the average deviation values. Generalized linear model analysis was used to compare the deviations within implant analogs for direct digital workflow, while 1-way analysis of variance and Dunnett's test were used to compare these analogs and conventional analogs (α = .05) Results. The analog design affected the linear deviations (y-axis), while the interaction between the analog design and the layer thickness, and the analog design affected the angular deviations (XY plane, P ≤ .030). S analogs had lower linear and angular deviations than N analogs, and S-50 led to lower angular deviations than N-50 (P ≤ .030). CNV led to higher linear accuracy (y-axis) than N-50, N-100, and S-100 and led to lower angular deviations than all test groups (XY plane) (P ≤ .025). The analogs in S-50 casts had positional trueness similar to or higher than those in other test groups and their accuracy was mostly similar to those in CNV casts. Implant analogs for direct digital workflow deviated more towards lingual and gingival, and conventional analogs deviated more towards buccal, occlusal, and distal. All analogs had a tendency to tilt towards lingual and distal.

Design, Synthesis, Docking Studies, and Biological Activity of Novel Analogs of Cyclophosphamide as Potential Anticancer Agents.

This study aimed to present the synthesis and characterization of four novel analogs of cyclophosphamide (2, 3, 4, 7) and their related precursors (1, 5, 6) and assess their anticancer activity against breast cancerous (MCF-7) and normal (HUVEC) cells. Notably, 2-(bis(2-chloroethyl)amino)-1,3,2-diazaphospholidine 2-oxide ((2)) and 2-(bis(2-hydroxyethyl)amino)-1,3,2-diazaphospholidine 2-oxide ((7)) exhibited concentration- dependent cytotoxicity against the MCF-7 cell line, with IC50 values of 8.98 and 28.74 μM, respectively. Annexin V/PI staining and ROS assays demonstrated reduced cell viability and mitochondrial dysfunction. in silico studies involving DFT-D optimization and Molegro virtual docking against B-DNA dodecamer and STAT3 receptors revealed enhanced interactions for certain compounds compared to cyclophosphamide. Importantly, the in silico and in vitro results corroborated each other, supporting the potential anticancer efficacy of these novel analogs.

Design of novel antimicrobial tetracycline analog by chemo-informatics

Design of novel antimicrobial tetracycline analog by chemo-informatics

Rationale design and synthesis of new roflumilast analogues as preferential selective and potent PDE-4B inhibitors

In this study, we designed and synthesized novel analogues of roflumilast that exhibit selective inhibition of PDE-4B. To accomplish this target; synthesis of novel series (4a-u, 5a-i, and 6) was done, aiming at obtaining new PDE-4B inhibitors hits based on the proposed pharmacophore, 1-(cyclopropylmethoxy)-2-(difluoromethoxy) benzene moiety. Enzyme assay was used to measure the IC50 values for the PDE-4B inhibition of all the synthesized compounds along with roflumilast as a reference drug. The results demonstrated that most of the examined candidates exhibited considerable inhibitory activity against the PDE-4B enzyme. The four compounds (4i, 4k, 4p, and 4q) exhibited the highest potency (IC50 = 7.25, 7.15, 5.50, 7.19 nM, respectively) with no significant inhibition difference from roflumilast (no statistical difference at p < 0.05). Interestingly, compound 4p with 3-OH and 4-OCH3 substituents was found to be the most potent against PDE-4B enzyme (IC50 = 5.50 nM), compared to that of roflumilast (IC50 = 2.36 nM). Moreover, the most potent derivatives 4i, 4k, 4p, and 4q were further tested for PDE-4D inhibitory activity to investigate their PDE-4D/PDE-4B selectivity ratio. Compound 4k showed the highest selectivity towards PDE-4B isozyme more than the reference drug roflumilast (PDE-4D/4B IC50 ratio for compound 4k and roflumilast = 3.22 and 3.02, respectively). Additionally, compound 4p was chosen to test its selectivity for PDE-4B over PDE-8A, PDE-11A, and PDE-1B compared to thereference drug roflumilast. Compound 4p showed approximately 6-fold selectivity for PDE-4B over PDE-8A, about 5-fold selectivity for PDE-4B over PDE-11A, and 11-fold selectivity of PDE-4B over PDE-1B. Compound 4p showed a higher selectivity towards PDE-4B than PDE-1B, more than the reference compound roflumilast. Furthermore, the most potent compounds (4i, 4k, 4p, 4q) were subjected to further investigation, and their effects on the cAMP level and percentage of inhibition of tumor necrosis factor-alpha (TNF-α) were studied and compared with reference drug roflumilast. Compound 4q showed the highest increase in the level of intracellular cAMP (6.55 ± 0.37 pmol/mL) and compound 4i showed the highest % of TNF-α inhibition (77.22 %). On the other side, a molecular docking study against PDE-4B clarified that all the examined candidates achieved nearly similar binding modes with similar orientations to that of the native roflumilast ligand and showed higher docking scores than roflumilast.

Design, Synthesis and Biological Evaluation of Novel Capsaicin Analogues Containing Heterocyclic Fatty Acids

AbstractThere is an urgent need to study safe and biocompatible medicinal compounds which necessitates the discovery of new agents from simple natural starting materials. In this study, eight novel capsaicin derivatives have been synthesized by combination of oxadiazole containing fatty acids with vanillyl amide. All the compounds were characterized by spectral analysis and were examined for their cytotoxicity, antimicrobial, antioxidant and anti‐inflammatory properties. The antioxidant activity of the synthesized derivatives was evaluated by 1,1‐diphenyl‐2‐picryl‐hydrazyl (DPPH) and thiobarbituric acid reactive substances (TBARS) assays. All of the synthesized derivatives have exhibited significant antioxidant activity in comparison to butylated hydroxy toluene (BHT) which is used as a reference antioxidant. The novel capsaicin derivatives with nitro (8 e) and methoxy substituents (8 f, 8 g and 8 h) exhibited the most significant antioxidant activity compared with BHT. In cytotoxicity assay against three cell lines, the derivative with bromo substituent showed excellent activity against B16‐melanoma cancer cell line followed by nitro and methoxy analogs which showed promising activity against HepG2‐ hepato and DU145‐prostate cancer cell lines respectively. In addition, all the derivatives exhibited moderate broad spectrum antibacterial, antifungal and anti‐inflammatory activity.

Novel Collagen Analogs with Multicopy Mucin-Type Sequences for Multifunctional Enhancement Properties Using SUMO Fusion Tags.

Multifunctional enhanced collagen materials in green biomanufacturing are highly desired yet challenging due to the poor comprehensive performance caused by the adoption of targeting monofunctional peptides. Herein, novel collagen analog design strategy using multicopy tandem of mucin-type sequence (GAPGAPGSQGAPGLQ) derived from human COL1α1 to construct basic building blocks is reported, in which SUMO tag is added to the N-terminal of the protein as a stabilizing core. In particular, novel collagen analogs (named S1506, S1511, S1523, and S1552) with multicopy mucin-type sequences (repeated 6, 11, 23, and 52 times), which were constructed in Escherichia coli, have distinct orientation preferences of functional enhancement (including cell proliferation, differentiation, migration, antioxidant activity, and anti-inflammatory property) compared to COL1α1 in HaCaT and THP-1 cell experiments due to variant three-dimensional structures (the different-length mucin-type polypeptide chains wind around central SUMO tag). Our findings suggest that the innovative protein design and synthesis approaches employed in the construction of these novel S15 proteins have the potential to advance the development of new types of recombinant collagen analogs.

Engineering Cu–Ce-a nanozymes: Revolutionary alloy nanomaterials mimicking cytochrome c oxidase for ultra-sensitive cytochrome c detection

The design of synthetic analogs of cytochrome c oxidase (CcO) is a formidable task due to its intricate structure encompassing multiple metal prosthetic sites and protein subunits. In recent years, artificial enzymes based on alloy nanomaterials have garnered significant attention due to the alloy design approach holds promise for the effective tuning of the properties of metal catalysts. In this study, we present copper-cerium alloy nanozymes (Cu–Ce-a NEs), where Cu mimics the active site of CcO, while Ce endows the alloy phase and enhances the capacity to catalyze the oxidation to cytochrome c (Cyt c). Cu–Ce-a NEs functionally mimics CcO, the terminal enzyme in the respiratory electron transport chain (ETC), by catalyzing the four-electron reduction of dioxygen to water. Utilizing the CcO-like properties of Cu–Ce-a NEs, we successfully implemented the electrochemical detection of Cyt c. The Cu–Ce-a NEs based electrochemical sensor revealed a favorable linear range spanning from 2 to 20 μM Cyt c, with a detection limit (LOD) of 2 μM. This method demonstrates high accuracy in Cyt c quantitation in pharmaceuticals, with results closely aligning with the actual concentrations. This finding not only offers new perspectives in the design of enzyme analogs, but also underscores the potential of this method for clinical Cyt c detection, highlighting its significance in biomedical research and diagnostics.

Novel purine derivatives as selective CDK2 inhibitors with potential anticancer activities: Design, synthesis and biological evaluation

Purine analogues were discovered to be inhibitors of CDK2, suggesting a potential therapeutic scaffold. This paper addresses the design, synthesis, and anticancer evaluation of purine analogues as kinase inhibitors. In the early stages of the investigation, the designed compounds demonstrated a promising docking score and greater protein–ligand stability in MD simulation than the standard, indicating a higher affinity against CDK2. Thus, we synthesised new purine analogues under simple and optimised reaction conditions. Among the studies under NCI-60, 5g and 5i were the most effective, with a percentage GI of 98.09 and 90 against OVCAR-4 and SNB-75, respectively, at a dose of 10 µM. Additionally, 5g and 5i demonstrated 7.80-fold and 1.54-fold greater cytotoxicity against PA-1 and MCF-7, with IC50s of 1.08 µM and 3.54 µM, respectively, compared to seliciclib (8.43 µM and 5.46 µM). In addition, 5g and 5i showed selective cytotoxicity against PA-1 and MCF-7 than normal cells, with selectivity indexes of 26.40 and 15.45, respectively, as compared to the standard (SI=3.83 and 5.91). In the kinase selectivity assay, both compounds demonstrated greater affinity against CDK2 than other kinases, with IC50 of 0.21 µM and 0.59 µM, in contrast to the standard (IC50 = 0.63 µM). Furthermore, 5g confirmed kinase inhibition in the western blot by lowering CDK2, cyclin A2, and other downstream substrates. Moreover, it triggered cell death by apoptosis and cell cycle arrest in G2/M. Taken together, 5g merits further investigation in PKPD research to discover a potential therapeutic candidate against cancer.

Toward Memory-Efficient Analog Design Using Precomputed Lookup Tables

Analog design productivity remains a challenge in the digitally driven semiconductor chip design field. Knowledge-based and simulation-based analog automation approaches have not achieved widespread acceptance in the analog design community. Systematic analog design using precomputed lookup tables (LUTs) is a promising approach that can address the design productivity challenge. Although modern computing systems have powerful memory capabilities, which make the LUT approach viable, reducing the memory footprint of the LUTs remains a challenge. A memory-efficient design technique using LUTs is proposed by using an incomplete grid in the MOSFET degrees-of-freedom (DoFs) space. An efficient indexing technique for the incomplete grid is also proposed, using a precomputed offset array in various scenarios, such as two-sided constraints and three-dimensional LUTs. The results show that the proposed technique can achieve up to a 67% reduction in memory footprint, in addition to improving LUT generation time and query performance.

The Fold as a Design Strategy: Analogy between Architecture and Issey Miyake’s Work

There is a notable similarity between the objectives of Architecture and Fashion Design. Both disciplines aim to protect and establish a sense of identity for their users. Similarly, analogous design strategies may be employed. One such strategy is the fold. The act of folding a surface results in the formation of a three-dimensional volume. The intrinsic two-dimensionality of the surface gives rise to the formation of space, which is characterised by three dimensions. The air that is trapped by the envelope provides the necessary space for the users. In the context of clothing, the enclosed space is relatively limited and personal. In contrast, in the field of Architecture, the space is of a larger scale and serves a collective purpose, accommodating a variety of activities. Consequently, the processes of designing a building or a piece of clothing are analogous, differing only in terms of scale, time, and materials. The employment of the fold as a point of departure for architectural and Fashion Design projects entails a comparable design process in which concepts such as continuity, superposition, and faceting are associated with this folded mechanism. Consequently, the resulting outcomes, particularly those pertaining to mass and aesthetic perception, exhibit notable similarities.

Design, synthesis, evaluation, pharmacophore modeling, and 3D-QSAR of lappaconitine analogs as potential analgesic agents.

Alleviating pain is crucial for patients with various diseases. This study aimed to enhance the analgesic properties of lappaconitine, a natural drug, through structural modifications. Specifically, carbamate analgesic active fragments were innovatively introduced at multiple sites on the benzene ring of lappaconitine. A total of 53 lappaconitine analogs were synthesized and evaluated. Compounds 5a, 5c, 5e, 6, and 15j addressed the narrow therapeutic window of lappaconitine, enhancing drug safety. Notably, carbamate analogs exhibited significantly enhanced analgesic activity, with compounds 5a and 5c having ED50 values of 1.2 and 1.6 mg/kg, respectively, indicating higher potency than lappaconitine (3.5 mg/kg). A metabolic analysis of compound 5e was conducted in mice, revealing its primary metabolic processes and metabolites, and providing preliminary exploration for the druggability. Given the multiple analgesic targets of lappaconitine, its analgesic mechanism remains inconclusive. This study, for the first time, analyzed the pharmacological activity characteristics of the lappaconitine analogs using a pharmacophore model and established a three-dimensional quantitative structure-activity relationship (3D-QSAR) to elucidate the quantitative relationship between the structures of the synthesized compounds and their analgesic activities. These findings provide valuable guidance for future structural modification and optimization of analgesic drugs.

Design, synthesis, biological evaluation and molecular docking study of thiadiazole-isatin hybrid analogues as potential anti-diabetic and anti-bacterial agents

We have synthesized thiadiazole-isatin hybrid analogues (1–20), characterized through different spectroscopic techniques such as 1HNMR, 13CNMR, HREI-MS, and evaluated against α-glucosidase and α-amylase enzymes. All analogues showed potent inhibitory potentials, having an IC50 values ranged from 22.08 ± 0.09 to 54.03 ± 0.07 μM (against α-amylase) and 19.03 ± 0.04 to 50.03 ± 0.02 μM (α-glucosidase) when compared with the standard drug acarbose (IC50 = 22.07 ± 0.02 μM for α-amylase and IC50 = 18.01 ± 0.06 μM for α-glucosidase respectively). Among the series, analogues 13 (IC50 = 19.03 ± 0.04 and 22.08 ± 0.09 μM), 12 (IC50 = 21.03 ± 0.07 and 24.03 ± 0.07 μM), and 5 (IC50 = 22.02 ± 0.03 and 26.02 ± 0.04 μM) were identified as the most active inhibitors. The structure–activity relationship was carried out, mainly associated with the nature, number, position, and electron-donating and electron-withdrawing effects of the substituent (s) on the phenyl ring. With the help of molecular docking, the binding interaction of the most active analogues within the active site of enzymes was confirmed. Almost twelve compounds were also screened for antibacterial potential, and few were found to be effective against Bacillus subtilis. All compounds were verified for cytotoxicity against the 3 T3 mouse fibroblast cell line and detected non-toxic.