Compounds 4g Research Articles

Insight on Some Newly Synthesized Trisubstituted Imidazolinones as VEGFR-2 Inhibitors.

Two series of ten new 1,2,4-trisubstituted imidazolin-5-ones were synthesized and screened against MCF-7 breast cancer and A549 lung cancer cell lines to test their potential in vitro anticancer activity. The results revealed preferential activity of the tested compounds toward MCF-7 cell lines compared to A549 cell lines. The most promising ten compounds (3a, 3c, 3f, 3g, 3h, 3i, 3j, 6a, 6f, and 6i) were subjected to VEGFR-2 enzyme inhibitory activity testing to further explore their mechanism of action. The tested compounds showed remarkable enzyme inhibition in micromolar concentrations ranging from 0.07 to 0.36 μM, compared with Sorafenib and Sunitinib with IC50 values of 0.06 and 0.12 μM, respectively. The most promising candidate, 3j, was further evaluated for its cell cycle phases, apoptotic induction ability, as well as its antiproliferative activity and inhibitory potential for endothelial cell migration, analyzed by a cell scratch assay. Furthermore, in silico studies were also performed to identify and detect the stability of the binding poses.

Design, synthesis, and structure–activity relationship of 2-chloro-3-formylquinoline containing hybrids as powerful antibacterial agents

This work aims to evaluate the antimicrobial activity of some new quinoline derivatives linked to pyrazole derivatives. The target compounds pyrazolylvinylquinoline 11a-g and 12a-g were achieved by the reaction of 2-chloro-6-nitro-3-quinolinecarboxaldehyde (4) with bromotriphenylphosphonylmethylpyrazole derivatives 9a,b to give the new quinoline derivatives 10a,b which in turn reacted with different aryl amines to afford 11a-g and 12a-g. Pyrazole derivatives 9a,b were obtained by the reaction of hydroxymethylpyrazole derivatives 8a,b with triphenylphosphine hydrobromide. Antimicrobial evaluation of the newly synthesized compounds showed that most of the new compounds appeared active toward Gram-positive bacteria more than Gram-negative bacteria. The biological evaluation of compounds 12d-g displayed the highest antimicrobial activity against the tested microorganism strains. Additionally, compounds 12d and 12f showed excellent activity against P. aeruginosa (MIC50 0.019 mg/mL), while compounds 11d, 11f, 12e, and 12g displayed good activity against the same microorganism (MIC50 0.07 mg/mL). On the other hand, most of the new compounds have moderate activity against E. coli. Compounds 12d and 12f showed excellent activity versus C. albicans in vitro antifungal activity (MIC50 0.15 mg/mL) comparing to or slightly lower than that of Fluconazole. Using molecular docking simulations, we evaluated the binding affinities and interactions of four chosen derivatives 12d-g with a target PDB code 3WT0 protein.

Exploration of morpholine-thiophene hybrid thiosemicarbazones for the treatment of ureolytic bacterial infections via targeting urease enzyme: Synthesis, biochemical screening and computational analysis

An important component of the pathogenicity of potentially pathogenic bacteria in humans is the urease enzyme. In order to avoid the detrimental impact of ureolytic bacterial infections, the inhibition of urease enzyme appears to be an appealing approach. Therefore, in the current study, morpholine-thiophene hybrid thiosemicarbazone derivatives (5a-i) were designed, synthesized and characterized through FTIR, 1H NMR, 13C NMR spectroscopy and mass spectrometry. A range of substituents including electron-rich, electron-deficient and inductively electron-withdrawing groups on the thiophene ring was successfully tolerated. The synthesized derivatives were evaluated in vitro for their potential to inhibit urease enzyme using the indophenol method. The majority of compounds were noticeably more potent than the conventional inhibitor, thiourea. The lead inhibitor, 2-(1-(5-chlorothiophen-2-yl)ethylidene)-N-(2-morpholinoethyl)hydrazinecarbothioamide (5g) inhibited the urease in an uncompetitive manner with an IC50 value of 3.80 ± 1.9 µM. The findings of the docking studies demonstrated that compound 5g has a strong affinity for the urease active site. Significant docking scores and efficient binding free energies were displayed by the lead inhibitor. Finally, the ADME properties of lead inhibitor (5g) suggested the druglikeness behavior with zero violation.

Investigating the antibacterial potential of novel N-Boc isatin Schiff bases: Combining synthesis with in-vitro and in-silico studies

The abstract explores into the antibacterial efficacy of newly synthesized N-Boc isatin Schiff bases against a range of pathogenic bacteria, including multidrug-resistant strains. The characterization of the synthesized compounds was achieved through various spectroscopic methods including 1H NMR, 13C NMR, and HRMS techniques, providing detailed structural insights. The in vitro antibacterial assessments were conducted via the agar diffusion method, revealing that compounds 3a, 3d, 3g, and 3j exhibited potent activity against both gram-positive (B. subtilis, MRSA) and gram-negative (E. coli) bacterial strains, providing objective data on their effectiveness. Furthermore, compound 3j, which featured bromine substitution at C5 of N-allyl isatin, displayed significant inhibition zones of 27 mm and 20 mm against E. coli and VRE, respectively, surpassing the activity of ciprofloxacin used as a standard drug molecule, thereby providing specific results. The molecular docking studies against E. coli Peptide Deformylase complex further confirmed the antibacterial potential of the synthesized compounds, adding a scientific basis for their efficacy. Additionally, in silico ADME predictions indicated favourable oral bioavailability, highlighting the promise of N-Boc substituted isatin Schiff bases as potential candidates for the development of novel antibacterial agents, thus contributing to the objective evaluation of their pharmacokinetic properties. Consequently, our studies demonstrated that these compounds not only possess significant antibacterial activity but also show promising pharmacokinetic properties, positioning them as strong candidates for the development of new antibacterial agents.

Novel Pyrido[4,3-d]pyrimidine Derivatives as Potential Sterol 14α-Demethylase Inhibitors: Design, Synthesis, Inhibitory Activity, and Molecular Modeling.

Thirty-four new pyrido[4,3-d]pyrimidine analogs were designed, synthesized, and characterized. The crystal structures for compounds 2c and 4f were measured by means of X-ray diffraction of single crystals. The bioassay results showed that most target compounds exhibited good fungicidal activities against Pyricularia oryzae, Rhizoctonia cerealis, Sclerotinia sclerotiorum, Botrytis cinerea, and Penicillium italicum at 16 μg/mL. Compounds 2l, 2m, 4f, and 4g possessed better fungicidal activities than the commercial fungicide epoxiconazole against B. cinerea. Their half maximal effective concentration (EC50) values were 0.191, 0.487, 0.369, 0.586, and 0.670 μg/mL, respectively. Furthermore, the inhibitory activities of the bioactive compounds were determined against sterol 14α-demethylase (CYP51). The results displayed that they had prominent activities. Compounds 2l, 2m, 4f, and 4g also showed better inhibitory activities than epoxiconazole against CYP51. Their half maximal inhibitory concentration (IC50) values were 0.219, 0.602, 0.422, 0.726, and 0.802 μg/mL, respectively. The results of molecular dynamics (MD) simulations exhibited that compounds 2l and 4f possessed a stronger affinity to CYP51 than epoxiconazole.

Design, synthesis and molecular docking study of novel triazole–quinazolinone hybrids as antimalarial and antitubercular agents

In a quest to discover new antimalarial and antitubercular drugs, we have designed and synthesized a series of novel triazole–quinazolinone hybrids. The in vitro screening of the triazole–quinazolinone hybrid entities against the plasmodium species P. falciparum offered potent antimalarial molecules 6c, 6d, 6f, 6g, 6j &6k owing comparable activity to the reference drugs. Furthermore, the target compounds were evaluated in vitro against Mycobacterium tuberculosis (MTB) H37Rv strain. Among the screened compounds, 6c, 6d and 6l were found to be the most active molecules with a MIC values of 19.57–40.68 μM. The cytotoxicity of the most active compounds was studied against RAW 264.7 cell line by MTT assay and no toxicity was observed. The computational study including drug likeness and ADMET profiling, DFT, and molecular docking study was done to explore the features of target molecules. The compounds 6a, 6g, and 6k exhibited highest binding affinity of −10.3 kcal/mol with docked molecular targets from M. tuberculosis. Molecular docking study indicates that all the molecules are binding to the falcipain 2 protease (PDB: 6SSZ) of the P. falciparum. Our findings indicated that these new triazole–quinazolinone hybrids may be considered hit molecules for further optimization studies.

Indole-based thiosemicarbazones for neurodegenerative diseases as prolyl oligopeptidase inhibitors

One of the highly expressed enzymes in the brain, prolyl specific oligopeptidase (POP), is a key target for the treatment of illnesses of the central nervous system including, autism spectrum, schizophrenia, Parkinson's, dementia, and Alzheimer's. In the current studies we report a series of indole based thiosemicarbazone as prolyl oligopeptidase (POP) inhibitors. Numerous approaches, such as Fourier-transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), and mass-spectrometry (MS) procedures, were used to confirm the structures of all substances. These compounds were evaluated against POP interestingly all these tested molecules significantly inhibit POP in vitro at very low doses (5.74–25.30 µM). Compound 3g displayed the highest inhibition with IC50 value 5.74 ± 0.27 µM. Kinetic studies of compounds, 3g, revealed concentration dependent type of inhibition with Ki value 4.31 ± 0.0012 µM. Furthermore, molecular docking was also performed to understand the binding modes of compounds, which correlates with our in vitro outcomes.

Synthesis, Biological and Molecular Docking Studies of Thiazole-Thiadiazole derivatives as potential Anti-Tuberculosis Agents.

Tuberculosis remains a global health threat, with increasing infection rates and mortality despite existing anti-TB drugs. The present work focuses on the research findings regarding the development and evaluation of thiadiazole-linked thiazole derivatives as potential anti-tuberculosis agents. We present the synthesis data and confirm the compound structures using spectroscopic techniques. The current study reports twelve thiazole-thiadiazole compounds (5 a-5 l) for their anti-tuberculosis and related bioactivities. This paper emphasizes compounds 5 g, 5 i, and 5 l, which exhibited promising MIC values, leading to further in silico and interaction analysis. Pharmacophore mapping data included in the present analysis identified tubercular ThyX as potential drug targets. The compounds were evaluated for anti-tubercular activity using standard methods, revealing significant MIC values, particularly compound 5 l, with the best MIC value of 7.1285 μg/ml. Compounds 5 g and 5 i also demonstrated moderate to good MIC values against M. tuberculosis (H37Ra). Structural inspection of the docked poses revealed interactions such as hydrogen bonds, halogen bonds, and interactions containing Pi electron cloud, shedding light on conserved interactions with residues like Arg 95, Cys 43, His 69, and Arg 87 from the tubercular ThyX enzyme.

Antibiofilm effect of rubrolide analogues and derived lactams on single-species biofilms

In this study, a series of 26 lactones and lactams have been investigated for their effect against 14 single-species biofilm of oral commensal and pathogenic species (Streptococcus oralis, S. mitis, S. sanguinis, S. gordonii, Actinomyces naeslundii, A. viscosus, Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum, Porphyromonas gingivalis, Prevotella intermedia, Streptococcus mutans, S. sobrinus, S. salivarius, Veillonella parvula). At the dose of 128 mg/mL, all substances inhibited biofilm formation of S. oralis by more than 60 %, and 19 caused >60 % reduction in the biofilm production by S. sanguinis and A. naeslundi. In addition, 16 compounds showed better results against P. intermedia and F. nucleatum, inhibiting biofilm formation by > 50 %, while 8 compounds caused >40 % reduction in the biofilm formation of A. actinomycetemcomitans. Compounds 5b, 5c, 5d, 5f, and 7 g were the only ones active against S. mutans, and 6d was the only one active against S. sobrinus biofilm formation. Amongst all compounds tested, 24 maintained cell viability above 50 % after 24 h of exposure. In summary, a set of lactones and lactams capable of inhibiting single-species biofilms of oral commensal and pathogenic bacteria without showing significant cytotoxicity against oral epithelial cells were identified. These results highlight the potential of using such antibiofilm compounds as an alternative approach to control oral biofilms.

Rational design, synthesis, biological evaluation, and molecular modeling of novel naphthamide derivatives possessing potent, reversible, and competitive inhibitory mode of action over human monoamine oxidase.

Herein, a novel series of naphthamide derivatives has been rationally developed, synthesized, and evaluated for their inhibitory activity against monoamine oxidase (MAO) and cholinesterase (ChE) enzymes. Compared to the reported naphthalene-based hit IV, the new naphthamide hybrids 2a, 2c, 2g and 2h exhibited promising MAO inhibitory activities; with an IC50 value of 0.294μM, compound 2c most potently inhibited MAO-A, while compound 2g exhibited most potent MAO-B inhibitory activity with an IC50 value of 0.519μM. Compounds 2c and 2g showed selectivity index (SI) values of 6.02 for MAO-A and 2.94 for MAO-B, respectively. On the other hand, most compounds showed weak inhibitory activity against ChEs except 2a and 2h over butyrylcholinesterase (BChE). The most potent compounds 2c and 2g were found to be competitive and reversible MAO inhibitors based on kinetic and reversibility studies. Plausible interpretations of the observed biological effects were provided through molecular docking simulations. The drug-likeness predicted by SwissADME and Osiris property explorer showed that the most potent compounds (2a, 2c, 2g, and 2h) obey Lipinski's rule of five. Accordingly, in the context of neurological disorders, hybrids 2c and 2g may contribute to the identification of safe and potent therapeutic approaches in the near future.

An inexpensive, metal-free and one-pot approach towards N-sulfonyl amidines: Identification of a chorismate mutase inhibitor with activities against S. aureus

The simple yet innovative synthetic approaches for the direct access to the diversity based unique class of compounds of potential biological interest are of considerable interest as that can greatly facilitate the efforts in bioorganic / medicinal chemistry and drug discovery. In our efforts, we have developed a metal-free, inexpensive and one-pot method for the facile and direct synthesis of N-sulfonyl amidines that were designed as inhibitors of chorismate mutase. The methodology involved POCl3-SOCl2 promoted reaction of amide with sulphonamide to afford an array of new and unique class of compounds in good to acceptable yields. The methodology is free from the use of additional organic reaction media and amenable for scale-up. Based on in vitro and in silico studies, 3g has been identified as a first example of chorismate mutase inhibitor with selective and promising activities on a range of S. aureus strains. Indeed, the docking of 3g into AlphaFold predicted structure S. aureus CM I (UniProt ID: A0A380DU97) revealed good interactions with stabilization mostly via π-anion interactions in addition to a halogen (fluorine) bond. Compound 3g is of further pharmacological interest.

Synthesis and biological evaluation of new 2-Amino-7-hydroxy-8-methyl-4-aryl-4H-chromene-3-carbonitrile derivatives

A series of new 2-amino-7-hydroxy-8-methyl-4-aryl-4H-chromene-3-carbonitrile derivatives (4a-4g) have been synthesized by a one-pot multicomponent reaction of 2-methylresorcinol (1) and malononitrile (2) with various aldehydes (3). All the synthesised compounds (4a-4g) have been characterised using FT-IR, 1H NMR, 13C NMR, HR-MS and evaluated for swarming behaviour, biofilm formation, biofilm disruption and urease activity against P. mirabilis (MTCC-425). Among all the synthesized compounds, compounds 4a, 4b and 4g showed slightly inhibited swarming behaviour and compounds 4f and 4g inhibited biofilm formation with increasing concentration. SEM (Scanning Electron Microscope) imaging shows that compound 4e effectively disrupts the preformed biofilm. Also, compounds 4d and 4e showed 40% reduction in urease activity. The SAR studies of synthesized compounds are elaborated in detail to provide key structural features. Furthermore, molecular docking studies against urease could provide a mechanistic basis for the inhibition. The per-residue interaction analysis suggested the involvement of non-bonded and bonded interactions with the active site of urease. Hence, the aim of the below study was to synthesize new chromene derivatives and study their biological activities.

Synthesis of novel vicinal diaryl triazoles with sulfur and hydrazine linkers as highly potent anticancer and antioxidant agents

Heading the list of the critical health-related issues worldwide, cancer continues to be one of the most serious life-threatening diseases. Moreover, development of new antioxidants is a field of growing interest because some synthetic antioxidants such as BHA and BHT are now suspected to be potentially harmful to human health. Accordingly, two series of 1,2,4-triazole–ring-containing combretastatin analogs; 8a-j with sulfur linker and 9a-j with hydrazine linker were synthesized. All twenty compounds were tested in vitro for their anticancer activity on three different cancer cell lines including A549, MCF7, and HepG2. A superior cytotoxic activity of all compounds with sulfur linker (8) as compared to doxorubicin, on A549, MCF7 cancer cells, was observed. Furthermore, the best results against HepG2 were obtained for 8e, 8c, 8f and 8g. In addition, compound 8g has also exhibited strong binding affinity against estrogen receptor alpha through in silico molecular docking simulations. Moreover, the antioxidant activity of all derivatives was evaluated using FRAP assay and DPPH test. The compounds 8e, bearing 3,4,5‑methoxy phenyl moiety, and 9g, carrying fluorophenyl group, were the most potent radical scavengers in the DPPH method and also had the superior capacity in the FRAP assay.

Highly Efficient Bimetallic Catalyst for the Synthesis of N-substituted Decahydroacridine-1,8-diones and Xanthene-1,8-diones: Evaluation of their Biological Activity

Background: Bimetallic catalysis plays a major role in boosting the catalytic performance of monometallic counterparts due to the synergetic effect. Method and Materials: In the present study, we have exploited ZrCl4:Mg(ClO4)2 as an efficient bimetallic catalyst for the synthesis of a few biologically relevant N-substituted decahydroacridine-1,8-diones and xanthene-1,8-diones under solvent-free conditions. The complete characterization data (XRD, SEM, BET, pH, TGA, and IR) of the bimetallic catalyst, ZrCl4: Mg(ClO4)2, are provided in the supporting information. Results: Among the compounds screened for anti-oxidant and anti-microbial activities, the acridine derivatives with chloro and fluoro substitutions (compounds 4b, 4c, 4d, and 4j) have exhibited potent activities when compared to other compounds. Among the xanthene derivatives screened for anti-oxidant activity, compounds 5c, 5i, and 5j with chloro and nitro derivatives exhibited potent antioxidant activity, and the rest all showed moderately potent activity. Conclusion: Among the compounds screened for antibacterial activity, compound 5j with chloro substitution showed potent activity, followed by compounds 5c, 5d, 5h, and 5i against Gram +ve bacteria, and compounds 5h, 5f, and 5g with N,N-dimethyl, methoxy and hydroxy substitutions have shown potent activity against Gram -ve bacteria.

Design and Synthesis of Potent Anticancer Agents Using Coumarin‐Quinazolinone Based Scaffolds: Exploration of ADME Properties and Molecular Docking Studies

AbstractCancer remains a complex global threat causing widespread deaths. Developing effective anticancer agents despite advancements still remained challenging. In this work it is designed and synthesised therapeutically active anticancer agents based on coumarin‐quinazolinone 5(a–j) through nucleophilic substitution reaction of 4‐bromomethyl coumarin derivatives with 6,7‐bis(2‐methoxyethoxy)quinazolin‐4(3H)‐one and characterised by using FTIR, 1HNMR, 13C NMR and LCMS analysis. The compounds 5(a–j) were screened for in vitro anticancer activity against A‐549 lung cancer cell lines and MDA‐MB‐231 cell lines. Compound 5i emerged as the most promising antiproliferative candidate demonstrating an IC50 value of 7.11 μM against A‐549 cell lines. Meanwhile compound 5g found as a hit candidate in the case of MDA‐MB‐231, exhibiting an IC50 of 5.12 μM, surpassing the potency of the standard drug doxorubicin (IC50 5.89 μM). Further, the safety profile of coumarin‐quinazolinone scafolds (5a–j) were examined for their cytotoxicity towards human embryonic kidney cell lines (HEK293). It was found that the most active compounds exhibited good safety profile towards human embryonic cell lines. Additionally, molecular docking investigations confirmed that compounds 5(a–j) exhibited elevated docking scores and demonstrated favourable interactions with the HER2 (PDB:3PP0) and VEGFR2 (PDB:4ASE). Furthermore, we investigated the ADME properties using the SwissADME tool.

Synthesis and molecular docking studies of new aryl imeglimin derivatives as a potent antidiabetic agent in a diabetic zebrafish model

Diabetes mellitus (DM) is a persistent, progressive, and multifaceted disease characterized by elevated blood glucose levels. Type 2 diabetes mellitus is associated with a relative deficit in insulin mainly due to beta cell dysfunction and peripheral insulin resistance. Metformin has been widely prescribed as a primary treatment option to address this condition. On the other hand, an emerging glucose-reducing agent known as imeglimin has garnered attention due to its similarity to metformin in terms of chemical structure. In this study, an innovative series of imeglimin derivatives, labeled 3(a–j), were synthesized through a one-step reaction involving an aldehyde and metformin. The chemical structures of these derivatives were thoroughly characterized using ESI–MS, 1H, and 13C NMR spectroscopy. In vivo tests on a zebrafish diabetic model were used to evaluate the efficacy of the synthesized compounds. All compounds 3(a–j) showed significant antidiabetic effects. It is worth mentioning that compounds 3b (FBS = 72.3 ± 7.2 mg/dL) and 3g (FBS = 72.7 ± 4.3 mg/dL) have antidiabetic effects comparable to those of the standard drugs metformin (FBS = 74.0 ± 5.1 mg/dL) and imeglimin (82.3 ± 5.2 mg/dL). In addition, a docking study was performed to predict the possible interactions between the synthesized compounds and both SIRT1 and GSK-3β targets. The docking results were in good agreement with the experimental assay results.

Synthesis and anti-breast cancer evaluation of fused imidazole-imidazo[1,2-c][1,2,3]triazoles: PEG-400 mediated one-pot reaction under ultrasonic irradiation

Synthetic chemists have organized easy and effective ways for perfect synthesis in response to the requirement for scaffolds that are crucial for medical applications. To investigate the synthesis of fused 1,2,3-triazoles in the presence of ultrasound, the [3 + 2] cycloaddition followed by CN bond formation reaction between 2-chloro-N-(1-methyl-1H-imidazol-2-yl)acetamide and substituted aryl iodoalkynes was carried out ourpreviously reported condition. The cancer activity of the synthesized compounds were then tested in vitro against two breast cancer cell lines MCF-7 and MDA-MB231 and some of the compounds 5g and 5j showed more potent activity against MCF-7 compared to standard erlotinib (IC50 = 4.70 ± 0.11 μM) with IC50 values 4.02 ± 0.74 and 4.23 ± 0.65 μM. Later, in vitro EGFR results revealed that compound 5g (IC50 = 0.38 ± 0.02 μM) have shown more effective than the conventional medicine erlotinib (IC50 = 0.42 ± 0.04 μM). Compounds 5j (IC50 = 0.42 ± 0.05 μM) have shown equipotent, 5i (IC50 = 0.53 ± 0.02 μM) and 5k (IC50 = 0.58 ± 0.02 μM) were shown good activity compared to the standard erlotinib. In silico investigations of more potent compounds (5g, 5i, 5j, 5k, and 5q) and erlotinib on the EGFR protein indicated that all five compounds had comparable binding energies and inhibition constants than the erlotinib.

Design, synthesis, molecular docking, and molecular dynamic studies of novel quinazoline derivatives as phosphodiesterase 7 inhibitors.

Introduction: Phosphodiesterase 7 (PDE7) is a high-affinity cyclic AMP (cAMP)-specific PDE that is expressed in immune and proinflammatory cells. In this work, we explore the possibility that selective small molecule inhibitors of this enzyme family could provide a novel approach to alleviate the inflammation that is associated with many inflammatory diseases. Methods: A series of novel substituted 4-hydrazinoquinazoline derivatives and fused triazoloquinazolines were designed, synthesized, and evaluated in vitro for their PDE7A inhibition activities, in comparison with Theophylline, a non-selective PDE inhibitor, and BRL50481, a selective PDE7A inhibitor. This series of novel quinazoline derivatives were synthesized via multi-step reactions. The reaction sequence began with selective monohydrazinolysis of compounds 2a,b to give 3a,b. Schiff bases 4a-h were synthesized by the reaction of the quinazolylhydrazines 3a,b with various substituted aromatic aldehydes. The reaction of 4a-h with bromine in acetic acid, in turn, gave fused triazoloquinazolines 5a-h. These compounds were characterized by satisfied spectrum analyses mainly including 1HNMR, 13CNMR, and MS together with elemental analyses. Results and discussion: The results of in vitro PDE7A inhibition activity clearly indicated that compounds 4b, 4g, 5c, and 5f exhibited good potency. Molecular docking and molecular dynamic simulation studies further supported our findings and provided the basis of interaction in terms of conventional hydrogen bonds and π-π stacking patterns. The present results lay the groundwork for developing lead compounds with improved phosphodiesterase seven inhibitory activities.

Multi Targeted Ligands for Potential Inhibition of Dipeptidyl Peptidase 4, Acetylcholinesterase and Cyclooxygenase 2

Two series of novel compounds were designed by combining indomethacin and ibuprofen with sixteen sulfa drugs. These compounds were systematically evaluated through target fishing using the Pharm Mapper, leading to the identification of DPP-4, AChE, and COX-2 as potential targets. Molecular docking was performed to evaluate the binding affinity of designed compounds against the identified three target proteins. The results revealed that the designed compounds exhibited binding affinities ranging from ~8 to -12kcal/mol, 12 to 13 kcal/mol and 8 to 11kcal/mol for DPP-4, AChE and COX-2 respectively. The binding affinities were found to be comparable or higher than binding affinity of co-crystallized ligand, which was found to be ~10, 12 and 9 kcal/mol respectively. Further investigation into the binding modes of these compounds was carried out. Notably, for DPP-4 complexes, interactions with Arg125, Glu205, and Glu206 were observed which are essential for substrate and inhibitor binding. For AChE complexes, interactions involved crucial His447 residues, essential for acetylcholine hydrolysis. In the case of COX-2, hydrogen bond interaction was noted with Arg120 located at the entrance of the hydrophobic channel. Despite favorable binding potentials, ADME profiling highlighted five compounds (1A, 1F, 1G, 1H, and 1O) with drug-like characteristics but lacking blood-brain barrier permeation ability. Out of five compounds, 1H stood out, demonstrating superior binding affinity and interactions vital residues necessary for catalytic activity of three enzymes. Thus, 1H emerges as a promising candidate for Multi-Targeted Drug-Like (MTDL) development aimed at addressing diabetes mellitus related dementia.

Statine-based peptidomimetic compounds as inhibitors for SARS-CoV-2 main protease (SARS-CoV‑2 Mpro)

COVID-19 is a multisystemic disease caused by the SARS-CoV-2 airborne virus, a member of the Coronaviridae family. It has a positive sense single-stranded RNA genome and encodes two non-structural proteins through viral cysteine-proteases processing. Blocking this step is crucial to control virus replication. In this work, we reported the synthesis of 23 statine-based peptidomimetics to determine their ability to inhibit the main protease (Mpro) activity of SARS-CoV-2. Among the 23 peptidomimetics, 15 compounds effectively inhibited Mpro activity by 50% or more, while three compounds (7d, 8e, and 9g) exhibited maximum inhibition above 70% and IC50 < 1 µM. Compounds 7d, 8e, and 9g inhibited roughly 80% of SARS-CoV-2 replication and proved no cytotoxicity. Molecular docking simulations show putative hydrogen bond and hydrophobic interactions between specific amino acids and these inhibitors. Molecular dynamics simulations further confirmed the stability and persisting interactions in Mpro's subsites, exhibiting favorable free energy binding (ΔGbind) values. These findings suggest the statine-based peptidomimetics as potential therapeutic agents against SARS-CoV-2 by targeting Mpro.