Synthesis, structure activity relationship and molecular docking studies of novel 2-aminothiadiazole analogues as dual α-glucosidase and α-amylase inhibitors with antibacterial activity

This research work focuses on the development of Phenylpropanoid Sucrose Esters (PSEs) as lead antidiabetic Alpha Glucosidase Inhibitors (AGIs) with the ultimate aim of eliminating the side effects associated with the current commercial drugs (Acarbose, Miglitol and Voglibose). Structure Activity Relationship (SAR) studies (in vitro, in silico and in vivo) have been used to guide this aim. In vitro inhibition studies indicate that most of our PSEs (feruloyl, coumaroyl and cinnamoyl) are much better than the standard drug Acarbose in inhibiting α-glucosidase. The IC50 values for the most active PSEs range from 4 to 9μM as compared to 328μM for Acarbose. Most of the PSEs examined show less inhibition of α-amylase in comparison to Acarbose and the most active PSEs have IC50 values comparable to Acarbose (0.7-2μM for the PSEs and 5μM for Acarbose). This indicates a greater selectivity of the PSEs towards α-glucosidase than α-amylase. This selectivity is thought to play important role in reducing the GI side effects that accompany the AGIs. From the in vitro studies, we can conclude that the type, position and number of phenylpropanoid substituents on the sucrose core, the aromatic ‘OH’ group, and the diisopropylidene rings greatly affect the anti-diabetic activity of the PSEs. Molecular docking studies of the PSEs show excellent correlation with the experimental data. From the binding mode pictures, we can conclude that the presence of free ‘OH’ groups on the aromatic substituents and the substitution at position 3 on sucrose core are critical for inhibition. PSEs dock close to the active site of α-glucosidase. Docking with α-amylase indicate multiple binding sites. PSEs where all four substituent groups interact with the amino acid residues at the catalytic site show a higher inhibition. Inhibition kinetic studies of all PSEs show mixed inhibition of the enzyme, α-glucosidase. All of the PSEs show a mixed partial type of inhibition of α-amylase except PSE 4FI (uncompetitive). One lead drug, PSE 4FI was selected to test its ability to mitigate post prandial hyperglycemia in vivo. Administration of the drug orally with starch is seen to reduce the increase in blood glucose levels following an oral starch tolerance test in STZ treated mice. PSE 4FI is as effective as Acarbose in reducing the surge in blood glucose after a starch load in the test mice. Further SAR studies were conducted with newly synthesized PSEs to identify the characteristics of the ideal PSE AGI. We conclude that the structural features essential to the anti-diabetic activity of the PSEs are found to be: four substituents on the sucrose core, alkenyl C=C, phenyl ring, diisopropylidene ring and the aromatic ‘OH’ groups. The most effective hydroxycinnamic acid substituents are the feruloyl and the caffeoyl moieties.

In an effort to design and synthesize a new class of α-glucosidase and α-amylase inhibitors, we have synthesized novel pyrrole based molecules using molecular hybridization approach. These novel analogs were synthesized by the novel methodology developed in our lab which comprises of the multi-component direct synthesis route using hypervalent iodine reagent. The compounds were characterized by infrared, 1H nuclear magnetic resonance (NMR), 13C NMR and Mass Spectroscopy. These compounds were screened for their α-amylase and α- glucosidase activity. They showed a varying degree of inhibition with IC50 values ranging between 0.4 to 4.14 µmol/mL and 0.8 to 4.14 µmol/mL for α-amylase and α-glucosidase respectively. Compounds 3, 7, 12, and 18 showed excellent activity as compared to standard acarbose. This has identified a new class of α-amylase and α-glucosidase inhibitor which can be further developed as antihyperglycemic agents. The molecular docking analysis was carried out to better understand of interaction between α-amylase and α-glucosidase target and inhibitors in this series. We also generated a homology model for human α-glucosidase enzyme and identified the key residues at the binding site. The outcome of the study could be used for the rational design of potent and selective α-amylase and α-glucosidase inhibitors, respectively.

In the present study, a series of 2-amino-4,6-diarylpyrimidine derivatives was designed, synthesized, characterized and evaluated for their in vitro α-glucosidase and α-amylase enzyme inhibition assays. The outcomes proved that this class of compounds exhibit considerable inhibitory activity against both enzymes. Among the target compounds, compounds 4p and 6p demonstrated the most potent dual inhibition with IC50 = 0.087 ± 0.01 μM for α-glucosidase; 0.189 ± 0.02 μM for α-amylase and IC50 = 0.095 ± 0.03 μM for α-glucosidase; 0.214 ± 0.03 μM for α-amylase, respectively as compared to the standard rutin (IC50 = 0.192 ± 0.02 μM for α-glucosidase and 0.224 ± 0.02 μM for α-amylase). Remarkably, the enzyme inhibition results indicate that test compounds have stronger inhibitory effect on the target enzymes than the positive control, with a significantly lower IC50 value. Moreover, these series of compounds were found to inhibit α-glucosidase activity in a reversible mixed-type manner with IC50 between 0.087 ± 0.01 μM to 1.952 ± 0.26 μM. Furthermore, molecular docking studies were performed to affirm the binding interactions of this scaffold to the active sites of α-glucosidase and α-amylase enzymes. The quantitative structure–activity relationship (QSAR) investigations showed a strong association between 1p–15p structures and their inhibitory actions (IC50) with a correlation value (R 2) of 0.999916. Finally, molecular dynamic (MD) simulations were carried out to assess the dynamic behavior, stability of the protein–ligand complex, and binding affinity of the most active inhibitor 4p. The experimental and theoretical results therefore exposed a very good compatibility. Additionally, the drug-likeness assay revealed that some compounds exhibit a linear association with Lipinski’s rule of five, indicating good drug-likeness and bioactivity scores for pharmacological targets. Communicated by Ramaswamy H. Sarma

Introduction/Objective: The present work describes the synthesis, urease, and lipase inhibition, and Structure-Activity Relationship (SAR) studies of some novel benzimidazolonebridged heterocyclic compounds, including piperazine, thiophene, furan, thiosemicarbazide, thiadiazole, and triazole moieties. At the same time, this study also examines changes in urease and lipase enzyme inhibition activities resulting from the attachment of different heterocycles to the benzimidazolone ring. Methods: To elucidate the interactions of the synthesized compounds with the binding sites of urease and lipase enzymes, molecular docking studies were performed using the Schrödinger Suite package with the IFD protocol. These molecular docking studies supported the in vitro inhibition results. Results: All the synthesized compounds demonstrated excellent urease inhibition activity, with IC50 values between 0.16 ± 0.037 μM and 0.37±0.091 μM when compared with standard thiourea (0.51 ± 0.028 μM). Discussion: Compound 6a showed excellent lipase inhibition activity with an IC50 value of 0.003 ± 0.001 μM, while the standard drug Orlistat showed 0.25 ± 0.067 μM. Compounds 2b, 6a, 6b, 7a, 7b, and 8b showed higher lipase inhibition activity than the standard Orlistat, with IC50 values ranging from 0.003 ± 0.001 μM to 0.17 ± 0.021 μM. Conclusion: The compounds were observed to bind the active sites of both enzyme structures through various non-covalent interactions. Additionally, SAR studies demonstrate that triazolecontaining compounds (8a, b) showed the best urease inhibitory activity with IC50 values of 0.16 ± 0.037 μM and 0.26 ± 0.052 μM, and that thiosemicarbazide derivatives (6a, b) showed the best lipase inhibition with IC50 values of 0.003 ± 0.001 and 0.14 ± 0.02 μM.

Background: The use of medicinal plants as supplemental or alternative medicine is widespread around the world. For the development of new drugs, studies on these medicinal plants that include pharmacological and toxicological assessments are crucial. Objective: This work aimed to find the total phenolic and flavonoid content, antioxidant, antibacterial, and antidiabetic potential of the traditionally used medicinal plant Mimosa rubicaulis Lam. Methods: The in vitro antidiabetic potential of methanolic extract and its fractions of the roots of M. rubicaulis were performed via enzyme (α-glucosidase and α-amylase) inhibition assays. Antioxidant and anti-inflammatory activities were carried out using 2,2 Diphenyl-1-picrylhydrazyl (DPPH), and reactive oxygen species (ROS) inhibiting methods. Well diffusion method is applied for antibacterial activity. Results: The crude extract reported the highest inhibition activity against α-glucosidase with an IC50 value of 10.29 ± 0.35 μg/mL compared to the standard acarbose’s IC50 value of 5.653 ± 0.29 μg/mL. Similarly, the ethyl acetate (EA) fraction disclosed significant inhibition against α-amylase with an IC50 value of 108.7 ± 0.66 μg/mL compared to the standard acarbose’s IC50 value of 6.01 ± 0.14 μg/mL. Likewise, the EA fraction showed the maximum antioxidant activity with an IC50 value of 11.89 ± 1.05 μg/mL among the crude extract and its fractions. Conclusion: Mimosa rubicaulis was found to have α-glucosidase and α-amylase inhibition, antiinflammatory, and antibacterial activity. To the best of our knowledge, this is the first report of α- glucosidase and α-amylase inhibition activity of this plant. Further studies on this plant are required to isolate potent compounds.

Synthesis of benzotriazoles derivatives and their dual potential as α-amylase and α-glucosidase inhibitors in vitro: Structure-activity relationship, molecular docking, and kinetic studies

Monoamine oxidase inhibitors: A concise review with special emphasis on structure activity relationship studies

In this study, hybrid analogs of benzimidazole containing a thiazole moiety (1–17) were afforded and then tested for their ability to inhibit α-amylase and α-glucosidase when compared to acarbose as a standard drug. The recently available analogs showed a wide variety of inhibitory potentials that ranged between 1.31 ± 0.05 and 38.60 ± 0.70 µM (against α-amylase) and between 2.71 ± 0.10 and 42.31 ± 0.70 µM (against α-glucosidase) under the positive control of acarbose (IC50 = 10.30 ± 0.20 µM against α-amylase) (IC50 = 9.80 ± 0.20 µM against α-glucosidase). A structure–activity relationship (SAR) study was carried out for all analogs based on substitution patterns around both rings B and C respectively. It was concluded from the SAR study that analogs bearing either substituent(s) of smaller size (−F and Cl) or substituent(s) capable of forming hydrogen bonding (−OH) with the catalytic residues of targeted enzymes enhanced the inhibitory potentials. Therefore, analogs 2 (bearing meta-fluoro substitution), 3 (having para-fluoro substitution) and 4 (with ortho-fluoro group) showed enhanced potency when evaluated against standard acarbose drug with IC50 values of 4.10 ± 0.10, 1.30 ± 0.05 and 1.90 ± 0.10 (against α-amylase) and 5.60 ± 0.10, 2.70 ± 0.10 and 2.90 ± 0.10 µM (against α-glucosidase), correspondingly. On the other hand, analogs bearing substituent(s) of either a bulky nature (−Br) or that are incapable of forming hydrogen bonds (−CH3) were found to lower the inhibitory potentials. In order to investigate the binding sites for synthetic analogs and how they interact with the active areas of both targeted enzymes, molecular docking studies were also conducted on the potent analogs. The results showed that these analogs adopted many important interactions with the active areas of enzymes. The precise structure of the newly synthesized compounds was confirmed using several spectroscopic techniques as NMR and HREI-MS.

Calcium/calmodulin‐stimulated adenylyl cyclase (AC) isoforms AC1 and AC8 are potential targets for treating chronic pain, opioid dependence, and anxiety. The objective of our study was to carry out a series of structure activity relationship (SAR) studies on selective inhibitors of AC1 and/or AC8 activity. Our lab has recently identified a selective inhibitor of AC1 activity, W001, that displayed anti‐allodynic properties in a mouse model of inflammatory pain. Moreover, we revealed that the effect of this compound was prevented by co‐administration of forskolin consistent with an in vivo effect on cAMP signaling. Despite these promising results, W001 also potentiated the activity of AC2 suggesting the potential for unwanted side effects. In an effort to achieve greater overall AC selectivity we undertook two approaches. In the first approach, we performed SAR studies using both commercially available and novel synthesized analogs of W001. The ability of these compounds to inhibit A23187 (calcium ionophore)‐stimulated AC1 activity was examined in HEK cells stably expressing AC1. Active compounds were subsequently evaluated on the closely related AC8 isoform and other representative ACs (i.e. AC2 and AC5). The SAR studies for W001's analogs revealed important structural elements that are important for its inhibitory activity as well as for its selectivity for AC1. Several W001 analogs showed inhibitory activity on both AC1 and AC8, and to date we identified one analog with modest selectivity for AC8 over AC1. This new tool compound may allow us to probe for the role of AC8 in mouse behavioral models. In the second approach toward identifying AC1 inhibitors, we completed a 10,000‐compound screen. We identified two promising scaffolds that have robust AC1 inhibitory activity with IC50 values in the low micromolar range (2–10 μM). These novel and diverse scaffolds revealed both AC1 selective and dual AC1/AC8 inhibition. Additionally, we have identified structural features that diminish the activity at other AC isoforms (e.g. potentiation of AC2). In addition to the SAR studies, an AC1 homology model was developed to predict the binding mode of W001, its analogs, and our newly identified scaffolds. The comparison of computational homology models of AC1 and AC8, in combination with the AC1 and AC8 SAR analyses, provided information about the inhibitor‐residue interactions responsible for the AC1 selectivity of W001. Lastly, we are evaluating our lead compounds in cellular models with the ultimate goal of testing them in animal models of neuropathic pain and opioid dependence. In conclusion, the SARs and molecular docking results indicate that AC1 and AC8 selective inhibition has a structural relationship; this information can be applied to the design and synthesis of more potent and selective AC inhibitors with drug‐like properties.Support or Funding InformationPurdue EVPRP, Indiana Clinical and Translational Sciences Institute (CTSI) and R21 MH101673/NIMH

A series of ten novel compounds were synthesized by incorporating a 1,3 thiazole core into amantadine and their structures were validated using different analytical and spectral methods such as FTIR, EI-MS, 1H NMR, and 13C NMR. The antibacterial and enzyme inhibitory properties of these newly synthesized compounds were evaluated. Remarkably, the compounds exhibited significant antibacterial activity against Escherichia coli and Bacillus subtilis. Additionally, the in vitro inhibitory activities of the synthesized compounds, against α-amylase, α-glucosidase, and urease were investigated. Among the tested compounds, compound 6d demonstrated potent and selective inhibition of α-amylase IC50 = 97.37 ± 1.52 μM, while acarbose was used as positive control and exhibited IC50 = 5.17 ± 0.25 μM. Compound 6d and 6e exhibited prominent inhibition against α-glucosidase IC50 = 38.73 ± 0.80 μM and 41.63 ± 0.26 μM respectively. Furthermore, compound 6d inhibited urease with exceptional efficacy IC50 = 32.76 μM, while positive control thiourea showed more prominent activity having IC50 = 1.334 μM. Molecular docking studies disclosed the binding mechanism and affinity of these new inhibitors within the binding sites of various amino acids. To investigate the association between molecular structural characteristics and inhibitory actions of synthesized derivatives, preliminary structure–activity relationship (SAR) studies were performed. These findings indicated that compounds 6a, 6c, 6d and 6e are potential candidates for hit-to-lead follow-up in the drug-discovery process for treating diabetes and hyperglycemia.

Dual α-amylase and α-glucosidase inhibitors: recent progress from natural and synthetic resources.

The development of multidrug resistant strains of extended-spectrum β-lactamase-producing Escherichia coli has become a global problem; therefore, the discovery of new antibacterial agents is the only available solution. To improve and propose new compounds with antibacterial activity, the three-dimensional quantitative structure-activity relationship and molecular docking studies were carried out on Aztreonam analogs as E. coli inhibitors in DNA gyrase B. This study's 3D-Quantitative structure-activity relationship model was created using on the Comparative Molecular Field Analysis and the Comparative Molecular Similarity Indices Analysis. Using the Comparative Molecular Field Analysis (Q 2 = 0.73; R 2 = 0.82), excellent predictability was achieved, and the best Comparative Molecular Similarity Indices Analysis model (Q 2 = 0.88; R 2 = 0.9). The generated model's ability to predict outcomes was assessed through external validation using a test set compound and an applicability domain technique. In this study, the steric, electrostatic, and hydrogen bond acceptor fields played a key role in antibacterial activity. The results of the molecular docking revealed that the newly generated compound A6 has the highest binding affinity with DNA gyrase B. It forms 10 hydrogen bonds with amino acid residues of Asn104, Asn274, Asn132, Ser70, Ser237, Thr105, Glu273, and 2 salt bridges with amino acid residues of Ser70 and Glu273 and one pi-pi interacting with Gys271 amino acid residue in the binding site of 5G1, and this result was validated by a new assessment method. We created some novel, highly effective DNA gyrase B inhibitors based on the earlier findings, and the most accurate model predicted their inhibitory actions. The ADMET characteristics and pharmacological similarity of these novel inhibitors were also examined. These findings would be very beneficial in guiding the optimization process for the identification of novel drugs that can address the issue of multiple drug resistance.

Rhus chinensis Mill, indigenous wild fruit primarily found in the hilly region of Nepal. The ripe fruit is very sour and considered medicinal as a remedy for colic pain. In addition, their astringent and styptic qualities are used internally to treat illnesses such as diarrhea and hemorrhage. Also, they are used as a common component of polyherbal medications for diabetic mellitus. This work aimed to determine the total phenolic and flavonoid content, antioxidant, antibacterial, α-glucosidase, and α-amylase inhibition activity of the crude extract and fractions of Rhus chinensis Mill. Additionally, molecular docking of compounds from Rhus chinensis was performed. Folin Ciocalteu's (FC) reagent was used to estimate total phenolic content. Likewise, the aluminium trichloride method was applied to determine total flavonoid content. A 2,2-diphenyl-1- picrylhydrazyl (DPPH) free radical scavenging assay was performed for the antioxidant activity. Furthermore, the substrate-based enzyme inhibition assay was carried out for α-glucosidase and α- amylase inhibition activity of R. chinensis. P-nitrophenyl-α-D-glucopyranoside (PNPG) and 2- Chloro-4-Nitrophenyl-α-D-Maltotrioside (CNPG3) were used as substrates for α-glucosidase and α- amylase inhibition assay, respectively. Similarly, the well-diffusion method was used for the antibacterial activity. Autodock vina was used to perform molecular docking. The total phenolic and flavonoid content of R. chinensis fruit were 117.092±1.1 mg GAE/g and 62.41±1.23 mg QE/g, respectively. The IC50 value for antioxidant activity of the crude extract and its fractions ranged from 3.12±1.15μg/mL to 50.85±2.10μg/mL. Similarly, the IC50 for α- glucosidase inhibition ranged from2.33±1.01μg/mL to 28.34±2.79μg/mL. Likewise, The IC50 of R. chinensis crude methanolic extract against α-amylase was 120.3±1.382μg/mL. The antibacterial activity of R. chinensis was effective against gram-positive bacteria; Staphylococcus aureus (ZOI=11.0) and Bacillus subtilis (ZOI=9.0). Quercetin-3-O-rhamnoside and Myricetin-3-Orhamnoside showed excellent binding to the active site of protein with binding energy -9.4kcal/mol and -9.6kcal/mol, respectively. Rhus chinensis Mill is a potent antioxidant and inhibits enzymes; α-glucosidase and α- amylase. In addition, the methanolic extract of this plant shows antibacterial activity. However, further research is required to determine the inhibiting compounds.

In the present work, a small library of novel pyrazolinyl-acyl thiourea (5a-j) was designed and synthesized through a multistep sequence and the synthesized compounds were screened for their antifungal, antibacterial and antioxidant activities as well as urease, amylase and α-glucosidase inhibitory activities. The synthesized series (5a-o) was characterized using a combination of spectroscopic techniques, including FT-IR, 1H NMR and 13C NMR. All compounds (5a-j) were found to have significant potency against urease, α-glucosidase, α-amylase, and DPPH. The synthesized compounds were also screened for potential antibacterial and anti-fungal inhibition activities. IC50 values for all the prepared compounds for urease, α-glucosidase, amylase, and DPPH inhibition were determined and derivatives 5b and 5g were found to be the most potent urease inhibitors with IC50 values of 54.2 ± 0.32 and 43.6 ± 0.25 μM, respectively. Whilst compound 5b (IC50 = 68.3 ± 0.11 μM) is a potent α-glucosidase inhibitor, compound 5f (90.3 ± 1.08 μM) is a potent amylase inhibitor and compound 5b (103.4 ± 1.15 μM) is a potent antioxidant. The different substitutions on the phenyl ring were the basis for structure-activity relationship (SAR) study. The molecular docking study was performed for the confirmation of binding interactions.

The indole scaffold has gained increasing importance due to its structural versatility and ability to interact with multiple cancerous receptors relevant to non-small cell lung cancer (NSCLC). So, the aim of this review is "Indole-Based Kinase Modulators for NSCLC: Recent Advances in Synthetic Route, Structure activity relationship (SAR) and Molecular Docking Studies for the betterment of future." Compilation of recently food and drug administration (FDA) approved indole-based drugs and molecular docking validation. In previously reported review they individually focused on the targets such as EGFR and the other targets. A systemic literature survey from 2020 to 2025 was done on the basis of indole as a main scaffold against different NSCLC targets. Data analysed from the given literature data. This review tells the key structural features of indole derivatives that will increase the kinase selectivity and potency against the EGFR, ALK, ROS1 and VEGFR targets. This review highlights indole scaffold as a core pharmacophore for multitargets against the NSCLC like EGFR, ALK/ROS1 and VEGFR. This review helps the medicinal chemist and other researchers to develop more indole-based molecules for muti kinase targets.