Compounds 4c Research Articles

Novel xylenyl-spaced bis-thiazoles/thiazines: synthesis, biological profile as herpes simplex virus type 1 inhibitors and in silico simulations.

Aims: Development of some potent bis-thiazole and bis-thiazine derivatives that could be used as antiviral prototypes. Materials & methods: Xylenyl-spaced bis-carbazone scaffold 3 was used as a versatile building block for bis-thiazole derivatives 6a-e and 9a-d and bis-thiazine derivatives 12a-f. These bis-heterocycles were screened as herpes simplex virus type 1 (HSV-1) inhibitors. Results: The new bis-heterocyclic compounds showed remarkable antiviral activity (e.g., compound 6d cytotoxicity concentration CC50 >500μg/ml). The antiviral capacity of the synthesized bis-compounds was supported by a molecular docking study against the glycoprotein D receptor of HSV-1. Compounds 6b, 9b, and 12c displayed the best binding coefficients. Conclusion: A new series of xylenyl-spaced bis-carbazone scaffolds were used as a building scaffold to construct a host of bis-thiazole/thiazine derivatives that could be used as antiviral prototypes.

New 1,2,3-triazole/1,2,4-triazole hybrids linked to oxime moiety as nitric oxide donor selective COX-2, aromatase, B-RAFV600E and EGFR inhibitors celecoxib analogs: design, synthesis, anti-inflammatory/anti-proliferative activities, apoptosis and molecular modeling study

A new series of bis-triazole 19a-l was synthesised for the purpose of being hybrid molecules with both anti-inflammatory and anti-cancer activities and assessed for cell cycle arrest, NO release. Compounds 19c, 19f, 19h, 19 l exhibited COX-2 selectivity indexes in the range of 18.48 to 49.38 compared to celecoxib S.I. = 21.10), inhibit MCF-7 with IC50 = 9–16 μM compared to tamoxifen (IC50 = 27.9 μM). and showed good inhibitory activity against HEP-3B with IC50 = 4.5–14 μM compared to sorafenib (IC50 = 3.5 μM) (HEP-3B). Moreover, derivatives 19e, 19j, 19k, 19 l inhibit HCT-116 with IC50 = 5.3–13.7 μM compared to 5-FU with IC50 = 4.8 μM (HCT-116). Compounds 19c, 19f, 19h, 19 l showed excellent inhibitory activity against A549 with IC50 = 3–4.5 μM compared to 5-FU with IC50 = 6 μM (A549). Compounds 19c, 19f, 19h, 19 l inhibit aromatase (IC50 of 22.40, 23.20, 22.70, 30.30 μM), EGFR (IC50 of 0.112, 0.205, 0.169 and 0.066 μM) and B-RAFV600E (IC50 of 0.09, 0.06, 0.07 and 0.05 μM).

Synthesis and biological evaluation of 1,3,4-oxadiazole Linked Thiazole-Isoxazole-Pyridines as anticancer agents

A new library of 1,3,4-oxadiazole moiety incorporated thiazol-isoxazol-pyridine derivatives (9a-j) have been synthesized and assessed for preliminary anticancer applications against four human cancer cell lines such as PC3 (prostate cancer), A549 (lung cancer), MCF-7 (breast cancer) and SiHa (cervix cancer) by using MTT method. The obtained results were compared with chemotherapeutic agent as etoposide. The results indicated that most of the derivatives exhibited more potent activities than with standard reference. The IC50 values ranges of the compounds from 0.01 ± 0.009 µM to 10.8 ± 6.23 µM, as well as standard showed IC50 values from 2.11 ± 0.024 µM to 3.11 ± 0.11 µM. Among all, compounds 9c, 9d, 9e, 9f and 9 g demonstrated more potency of activities than etoposide. In which one compound 9c showed good anticancer activity. Docking studies also presented for the compounds synthesized.

Design, synthesis and molecular dynamic studies of novel imidazo/pyrido-pyrimidine clubbed ethyl-1,2,3,4-tetrahydro-4-phenylpyrimidine-5-carboxylate derivatives as potent anti-tubercular agents

A small library of substituted ethyl-1,2,3,4-tetrahydro-4-phenylpyrimidine-5-carboxylate was designed and synthesized. All the characterized molecules were screened for their anti-tubercular activity using the H37Rv strain of Mycobacterium tuberculosis (Mtb). The compounds 5c, 5d, 5f, 5h, and 5k showed equipotent activity (MIC 3.12 µg/mL), compounds 5b, 5e, 5g, 5i, and 5j were more potent (MIC 1.6 µg/mL), whereas, 5a and 5l shown moderate activity (MIC 6.25 µg/mL). The potent inhibitory activity of screened compounds was rationalized with in-silico molecular modeling studies against the Mtb-dihydrofolate reductase (DHFR) enzyme. Compound 5i displayed a good docking score of −8.56 Kcal/mole with H-bond and hydrophobic interactions. These interactions revealed the stability of the complex which in turn determined the potent inhibitory effect. To get in-depth mechanistic insight into the inhibitory effect and to assess the stability of the ligand–protein complex, a molecular dynamics (MD) simulation study was performed. The RMSD and RMSF values obtained by the MD simulation study were 2.39 Å and 0.92 Å, respectively. The obtained values suggested that the drug–ligand complex maintained the stability over entire 100 ns run and the molecule did not fluctuate. The H-bond and hydrophobic interactions displayed in molecular docking studies were found to be retained in the MD simulation run. The obtained MD simulation values indicate that the complex was stable and rationalize the potent inhibitory effect. The drug-likeliness properties of potent compounds were calculated and the values thus obtained suggested that the molecule 5i has drug-likeliness properties and complies with Lipinski's rule of five/Ro3. Hence, the identified compounds can be taken into further stages of drug discovery processes.

Activity of Cinnamic Acid Derivatives with 4-Chloro-2-mercaptobenzenesulfonamide Moiety against Clinical HLAR and VRE Enterococcus spp.

The rapid increase in strains that are resistant to antibiotics requires new active compounds to be found whose mechanism of action on bacteria is different to those that are currently known. Of particular interest are compounds that occur in plants as secondary metabolites. The focus of this study concerns the examination of the effects of synthetic cinnamic acid derivatives, with 4-chloro-2-mercaptobenzenesulfonamide moiety on Enterococcus spp. with HLAR (high-level aminoglycoside resistance) and VRE (vancomycin-resistant Enterococcus) mechanisms. The minimum inhibitory concentration (MIC) values of the tested compounds were determined using the serial dilution method for Enterococcus spp. groups, and the most active compounds were as follows: 16d, 17c, 16a, 16c and 16f (2-4 µg/mL). These compounds, at a concentration of 4 × MIC, inhibited the biofilm formation of HLAR strains (70 to 94%). At concentrations of 2 × MIC and 4 × MIC, they also inhibited the growth of VRE strains (42 to 96%). The best effect produced on the formed biofilm was demonstrated by compound 16f (from 62% MIC concentration to 89% 4 × MIC concentration) on the tested HLAR strains. In vitro studies, using the peripheral blood of domestic sheep, demonstrated the stable bacteriostatic activity of the tested compounds against Enterococcus spp. The compounds 16a, 16c, 16d, 16f and 17c showed synergism and additivity with ampicillin, streptomycin, gentamicin and vancomycin against resistant strains of Enterococcus spp. The tested compounds, when combined, reduce the MIC for antibiotics by 800 to 10,000 times for HLAR strains and by 8 to 10,000 times for VRE strains. The MIC of the tested compounds, in combination with antibiotics, is reduced 2-16-fold for HLAR strains and 2-32-fold for VRE strains. These studies demonstrate the potential for the therapeutic use of synthetic, cinnamic acid derivatives, with 4-chloro-2-mercaptobenzenesulfonamide moiety, to work against clinical strains of Enterococcus spp.

Synthesis, Molecular Docking, and Anticancer Activity of N-Heteroaryl Substituted Flavon Derivatives

Background: Flavones are potential anticancer agents that act by different mechanisms and have multiple targets to exert anticancer effects. Nitrogen-containing heterocyclic rings have remarkable chemical characteristics as well as a wide range of biological activities. Substitution of the N-heterocyclic ring on the flavon structure may potentiate its anticancer effect. Objective: A series of flavon derivatives with an N-heteroaryl ring at the 4' position of the B ring of flavon were designed, prepared, and evaluated for anticancer activity. Methods: Different flavon derivatives were created by cyclizing chalcones, and chalcones were synthesized by Claisen-Schmidt condensation of substituted aldehydes and 2-hydroxyacetophenone. Structures of all compounds were confirmed by 1HNMR, 13CNMR, FTIR, and MS spectra. Molecular docking was used to study the binding interactions of the synthesized compounds with the multiple targets ER-α, EGFR, and VEGFR-2. Anticancer activity was evaluated by Brine shrimp assay, MTT assay, and SRB assay on breast cancer (MCF-7, MDA-MB-231, and MDA-MB-468) and cervical cancer (HeLa). An apoptosis study was carried out on MCF-7 cell lines for the active compounds. Results: Among all compounds, 6c and 5f showed potent growth inhibition of ER-positive breast cancer cell lines. Compounds 5b, 5c, 5g, and 6f displayed good anticancer activity against cervical cancer. In triple-negative breast cancer cell lines, compounds 5c, 6b, and 6c showed remarkable anticancer activity. The potent flavones identified against breast cancer cell lines were 5f and 6c. Anticancer study results were analogous to the results obtained by the molecular docking study. Conclusion: This study offers a viable reference point for improving the design of flavon-incorporated Nheterocyclic ring derivatives as anticancer compounds.

Synthetic Transformation of 4-fluorobenzoic Acid to 4-fluorobenzohydrazide Schiff Bases and 1,3,4-Oxadiazole Analogs having DPPH Radical Scavenging Potential

Aims: Synthesis of 4-fluorobenzohydrazide Schiff bases and 1,3,4-oxadiazole analogs has a DPPH radical scavenging potential. Background: Synthetic antioxidants are widely used because they are effective and cheaper than natural antioxidants. Based on the literature survey, this present study is mainly focused on the study of the free radical scavenging activity of the Schiff base and oxadiazole motifs. Methods: In this research work, Schiff’s base (4a-4g) and 1,3,4-oxadiazole (5a-5g) derivatives based on 4-fluorobenzoic acid were synthesized through multistep reactions. Initially, 4-fluorobenzoic acid was esterified in the presence of sulphuric acid (H2SO4) in ethanol solvent, and then it was reacted with an excess of hydrazine hydrate to obtain the desired 4-fluorobenzohydrazide. Various aromatic aldehydes were reacted with 4-fluorobenzo hydrazide in the presence of a catalytic amount of acetic acid to obtain the desired hydrazones. Finally, different substituted hydrazones were cyclized in the presence of iodine and potassium carbonate in DMSO to obtain substituted 1,3,4-oxadiazoles. The progress of all reactions was checked using thin-layer chromatography. The compounds were recrystallized from ethanol with good yield. The synthesized compounds were characterized with the help of EI-MS and 1H-NMR spectroscopy. Results: The synthesized Schiff bases (4a-4g) and oxadiazole derivatives (5a-5g) of 4-fluorobenzoic acid demonstrated good free radical scavenging activity. Among the series, Compound 4f (IC50 = 25.57 ± 7.41 μM), showed comparable activity when compared with the standard Vitamin C (IC50 = 19.39 ± 12.57 μM). Similarly Compound 4a (IC50 = 40.90 ± 1.92 μM), 4b (IC50 = 34.77 ± 1.03 μM), 4c (IC50 = 90.2 ± 2.90 μM), 4e (IC50 = 78.62 ± 9.64 μM), 4g (IC50 = 80.65 ± 1.80 μM), 5a (IC50 = 52.67 ± 4.98 μM) and 5f (IC50 = 89.45 ± 9.11 μM) showed moderate antioxidant activity. Furthermore compounds, 4d (IC50 = 102.55 ± 10.4 μM), 5b (IC50 = 123.76 ± 12.34 μM), 5d (IC50 = 701.62 ± 1.06 μM), and 5e (IC50 = 102.87 ± 7.98 μM) displayed less significant anti-oxidant potential, while compounds 5c and 5g were found inactive. Conclusion: Schiff’s base (4a-4g) and substituted 1,3,4-oxadiazole (5a-5g) derivatives based on 4- fluorobenzoic acid scaffolds were synthesized using standard pathways. All compounds were structurally characterized through EI-MS and 1H-NMR spectroscopy and evaluated for their in vitro DPPH free radical scavenging activity. In-vitro study reveals that the newly prepared derivatives of 4-fluorobenzoic acid have potent antioxidant potential. Whereas compound 5c and 5g were found inactive, this study has recognized a series of potential molecules as antioxidant agents and is useful in the field of medicinal chemistry.

Development of Dual Inhibitors of Soluble Epoxide Hydrolase/Fatty Acid Amide Hydrolase with Tetrazole Core.

The attractive biological actions of the eicosatrienoic acids (EETs) and endocannabinoids (eCBs) are terminated by means of enzymatic hydrolysis via soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) enzymes. Simultaneous inhibition of both enzymes is considered a novel approach in the treatment of inflammatory and neuropathic pain. In this study, a novel series of tetrazole derivatives as dual sEH/FAAH inhibitors were designed, synthesized, and biologically evaluated. Compounds 6c, 7d, and 8a, the most potent inhibitors against FAAH and sEH enzymes with acceptable IC50 values, significantly decreased carrageenan- induced paw edema 5h after carrageenan injection compared to the control group compound. In addition, compound 7d exhibited a significant reduction in pain scores compared to the control group. Docking studies showed that the presented dual inhibitors could bind to the essential residues in the catalytic sites of both enzymes. In silico prediction of several pharmacokinetic properties suggests that these dual inhibitors could potentially be orally active agents. These structures will be a valuable scaffold to develop soluble epoxide hydrolase inhibitors with dual potency towards fatty acid amide hydrolase.

Synthesis and Biological Evaluation of 1-Substituted (R)-6-(2?-Cyano-1?-Pyrrolidin-yl)-4-(3?- Hydroxyadamantan-1?-yl)-3-phenyl-1,2,4-triazines

A series of various 1-substituted (R)-6-(2?-cyano-1?-pyrrolidin-yl)-4-(3?-hydroxy adamantan-1?-yl)-3-phenyl- 1,2,4-triazines (5a-i) was synthesized by the reaction of (R)-6-(2?-cyano-1?-pyrrolidin-yl)-4-(3?-hydroxy adamantan-1?- yl)-3-phenyl-1,4-dihydro-1,2,4-triazine (4) with heterocyclic halogenated compounds (R-X) in the presence of potassium carbonate. All the synthesized compounds were evaluated biologically and also determined In vitro cytotoxicity of compounds 5a, 5c, 5d, 5e, 5g, and 5h against human cervical cancer cell line (HeLa). Among all the synthesized compounds, some compounds exhibited potent antimicrobial activity as well as cytotoxicity.. KEYWORDS :1,2,4-Triazine, Adamantanol, Biological activities, Pyrrolidine.

Evaluation of Cytotoxic, COX Inhibitory, and Antimicrobial Activities of Novel Isoxazole-carboxamide Derivatives

Abstract: Isoxazole derivatives are one of the heterocyclic structures that have various biological activities. Objective: This study aimed to design and synthesize novel isoxazole derivatives and evaluate their cytotoxic, cyclooxygenase (COX) inhibitory, and antimicrobial activities. Methods: Coupling reactions of aniline derivatives and isoxazole carboxylic acid have been established to synthesize chloro-fluorophenyl-isoxazole carboxamide derivatives. The synthesized compounds were characterized using 1H, 13C-NMR, IR, and HRMS spectrum analysis and evaluated by MTS, COX kit, and antimicrobial microdilution assays. Results: The synthesized compounds showed moderate to potent cytotoxic activity against all the screened cancer cell lines (except 2b against HepG2) with an IC50 range of 0.107-77.83 μg/ml. The results showed that the most potent compound against cervical cancer cell line (HeLa) was the 2b compound, with an IC50 value of 0.11±0.10 μg/ml, which is less than the IC50 for the potent anticancer drug Doxorubicin. While the 2a and 2b compounds have potential antiproliferative activities against Hep3B with IC50 doses of 2.774±0.53 and 3.621±1.56 μg/ml, respectively. Furthermore, 2c compound was the most active against MCF7, with an IC50 value of 1.59±1.60 μg/ml. In addition, the most potent isoxazole derivative against the COX1 enzyme was the 2b compound, with an IC50 value of 0.391 μg/ml, and compound 2a had a good selectivity ratio of 1.44 compared to the Ketoprofen positive control. However, compound 2c showed antifungal activity against Candida albicans with an MIC value of 2.0 mg/ml in comparison to the antifungal drug Fluconazole (MIC = 1.65 mg/ml). Conclusion: The synthesized compounds could be candidates for anticancer drugs in the future, and other analogues and cytotoxicity evaluations should be conducted.

Synthesis and Antidepressant Evaluation of Heteroaromatic derivatives of Gallic Acid

Oxidative stress is a causative factor of depression and several studies have reported that gallic acid or the derivatives thereof had proven to be effective in displaying antidepressant like action in animal models. Owing to the antioxidant property of GA and the study of structural features it was hypothesized to design new small molecule antidepressant drugs based on GA containing piperazine/piperidine. The two step reaction involved the formation of acid chloride of GA and its conversion to the target compounds in presence of acetone. All the compounds were subjected to evaluation of antidepressant effect using the widely used TST and FST models in mice at dose of 40mg/kg intraperitoneally. The synthesized compounds 2b, 2c and 2e were able to reduce the immobility time in both the models as comparable to the reference compound fluoxetine (10mg/kg) while compounds 2a and 2d were not very significant in reducing the immobility of mice.

1,3-Diphenylureido hydroxamate as a promising scaffold for generation of potent antimalarial histone deacetylase inhibitors

We report a series of 1,3-diphenylureido hydroxamate HDAC inhibitors evaluated against sensitive and drug-resistant P. falciparum strains. Compounds 8a–d show potent antiplasmodial activity, indicating that a phenyl spacer allows improved potency relative to cinnamyl and di-hydrocinnamyl linkers. In vitro, mechanistic studies demonstrated target activity for PfHDAC1 on a recombinant level, which agreed with cell quantification of the acetylated histone levels. Compounds 6c, 7c, and 8c, identified as the most active in phenotypic assays and PfHDAC1 enzymatic inhibition. Compound 8c stands out as a remarkable inhibitor, displaying an impressive 85% inhibition of PfHDAC1, with an IC50 value of 0.74 µM in the phenotypic screening on Pf3D7 and 0.8 µM against multidrug-resistant PfDd2 parasites. Despite its potent inhibition of PfHDAC1, 8c remains the least active on human HDAC1, displaying remarkable selectivity. In silico studies suggest that the phenyl linker has an ideal length in the series for permitting effective interactions of the hydroxamate with PfHDAC1 and that this compound series could bind as well as in HsHDAC1. Taken together, these results highlight the potential of diphenylurea hydroxamates as a privileged scaffold for the generation of potent antimalarial HDAC inhibitors with improved selectivity over human HDACs.

Synthesis and in Silico Studies of Some New 1,2,3-Triazolyltetrazole Bearing Indazole Derivatives as Potent Antimicrobial Agents.

1,2,3-Triazole and tetrazole derivatives bearing pyrrolidines are found to exhibit notable biological activity and have become useful scaffolds in medicinal chemistry for application in lead discovery and optimization. Novel indazole bearing 1,2,3-triazolyltetrazoles were designed as potential antimicrobial candidates. The structure of duel heterocyclics was validated by a spectroscopic technique of infrared (IR), nuclear magnetic resonance (1 H and 13 C NMR), and mass spectral data. Compounds 4b, 4c, 4d, and 4h were found to have a stronger antibacterial effect against Gram-positive (S. aureus, B. subtilis, M. Luteus) and Gram-negative (E. coli, P. aeruginosa) microorganisms with MICs ranging from 5±0.03-18±0.02 μM, respectively. Moreover, scaffolds 4a, 4h showed potent antifungal activity against A. flavus, M. gypsuem strains with MIC values of 10±0.02, 11±0.01 μM, which are similar activity that of the standard Itraconazole (MIC=8±0.02, 10±0.01 μM). The binding mode for compound 4 inside the catalytic pocket of S. aureus complexed with nicotinamide adenine dinucleotide phosphate and trimethoprim and produced a network of hydrophobic and hydrophilic interactions (3FRE). From in silico results, 4b demonstrated highly stable hydrogen binding amino acids Leu62(X) [N18…O, 2.47 Å], Arg44(X) [N17…N, 3.11 Å], Thr96(X) [N10…OG1, 3.05 Å], Gly94(X) [F7…N, 2.82 Å], and Gly43(X) [F7…N, 2.90 Å], which are plays a crucial role in ensuring efficient binding of the ligand in a crystal structure of antibacterial receptor. Furthermore, the physicochemical and ADME filtration molecular properties, estimation of toxicity, and bioactivity scores of these novel scaffolds were evaluated by using SwissADME and ADMETlab2.0 online protocols. Thus, the significant antimicrobial activity of indazole linked to duel heterocyclic compounds can be used for development of new antimicrobial agents with further modifications.

New pyrazolyl-thiazolidinone/thiazole derivatives as celecoxib/dasatinib analogues with selective COX-2, HER-2 and EGFR inhibitory effects: design, synthesis, anti-inflammatory/anti-proliferative activities, apoptosis, molecular modelling and ADME studies

Two new series of pyrazolyl-thiazolidinone/thiazole derivatives 16a–b and 18a–j were synthesised, merging the scaffolds of celecoxib and dasatinib. Compounds 16a, 16b and 18f inhibit COX-2 with S.I. 134.6, 26.08 and 42.13 respectively (celecoxib S.I. = 24.09). Compounds 16a, 16b, 18c, 18d and 18f inhibit MCF-7 with IC50 = 0.73–6.25 μM (dasatinib IC50 = 7.99 μM) and (doxorubicin IC50 = 3.1 μM) and inhibit A549 with IC50 = 1.64–14.3 μM (dasatinib IC50 = 11.8 μM and doxorubicin IC50 = 2.42 μM) with S.I. (F180/MCF7) of 33.15, 7.13, 18.72, 13.25 and 8.28 respectively higher than dasatinib (4.03) and doxorubicin (3.02) and S.I. (F180/A549) of 14.75, 12.96, 4.16, 7.07 and 18.88 respectively higher than that of dasatinib (S.I. = 2.72) and doxorubicin (S.I = 3.88). Derivatives 16a, 18c, 18d, 18f inhibit EGFR and HER-2 IC50 for EGFR of 0.043, 0.226, 0.388, 0.19 μM respectively and for HER-2 of 0.032, 0.144, 0.195, 0.201 μM respectively.

Tetrahydroisoquinoline-Triazole Derivatives: Novel Nicotinamide N-Methyltransferase Inhibitors

Through the Lilly Open Innovation Drug Discovery program (OIDD), we discovered five cationic bis(aryltriazol-4-yl)methyl)-6,7-dimethoxytetrahydroisoquinolinium derivatives that effectively inhibit human nicotinamide N-methyltransferase. Compounds 4a, 4c, and 4f demonstrated activity against hNNMT in enzymatic-based testing, with IC50 values of 3.177 μM, 7.9 μM, and 4.477 μM, respectively. In cell-based testing, 4c and 4f inhibited the enzyme in HEK293 cells with an IC50 value of 2.81 μM and 1.97 μM. Compound 4m inhibited hNNMT in the enzymatic-based assay by 98% at a concentration of 10 μM, with IC50 of 1.011 μM in the cell-based assay. Through structure-activity relationship analysis, we found that the active compounds had electron-withdrawing substituents at the 4-position of the phenyl-triazole, while compounds containing bulky and electron-donating groups at the same position did not display any activity. The results of docking studies using AutoDock 4.2 showed that all active compounds had similar binding patterns at the NNMT active site. They occupied the nicotinamide binding site and about two-thirds of the S-adenosyl-L-methionine site. However, the SAR and docking results of 4g contradicted the compound’s inactivity. Nevertheless, the molecular docking studies provided insight into how the ligands interact with the protein and explained the activity of our compounds.

Discovery of C-3 isoxazole substituted thiochromone S,S-dioxide derivatives as potent and selective inhibitors for monoamine oxidase B (MAO-B)

Developing new scaffolds for highly potent and selective inhibitors of human Monoamine Oxidase B (hMAO-B) is a crucial objective in enhancing the efficacy and safety in the clinical treatment of neurodegenerative diseases. In this study, we have identified a series of C-3 isoxazole-substituted thiochromone S,S-dioxide derivatives that exhibit strong inhibitory activity against hMAO-B. The strategy of oxidizing thiochromone to thiochromone S,S-dioxide solves the key defect of extreme insolubility observed for thiochromone analogues. In addition, the sulfone group contributes extra hydrogen(H)-bonding interactions with Tyr435, which significantly increases the activity of thiochromone S,S-dioxide derivatives against hMAO-B. Furthermore, the presence of isoxazole group provides potential H-bonding interaction and electrostatic interaction with the residue of Tyr326, while the rigid aryl ring introduces a potential steric conflict with Phe208 of hMAO-A to improve both potency and selectivity. In our investigations, several compounds (9c, 10c, 10e, 10g, 10l and 10m) demonstrate remarkable single-digit nanomolar potency. These compounds exhibit favorable cytotoxicity profiles in both differentiated SH-SY5Y and HVSMC cells, without apparent cardiotoxic effects. Moreover, compounds 10e and 10h do not lead to an increase in ROS levels in differentiated SH-SY5Y cells, further demonstrating their potential as safe and effective hMAO-B inhibitors. These findings indicate that the C-3 isoxazole substituted thiochromone S,S-dioxide analogues are potential leading compounds for the development of selective inhibitors with high potency.

Design and Synthesis of Substituted Anilino 6-(3,4,5-Trimethoxyphenyl)Pteridine Derivatives and Invitro Evaluation as Potential Cytotoxic Agents

A new library of target compounds (9a-j) was designed, synthesized, and fully characterized by 1HNMR, 13CNMR, and mass spectroscopy techniques. The target compounds were screened for their cytotoxic properties against cancer cell lines Colo-205, MCF-7, A549, and A2780 by employing the MTT assay, using the etoposide as the positive control. Among the newly synthesized target compounds, four compounds 9b-9d and 9j exhibited superior cytotoxic properties to the reference standard (etoposide). In particular, compound 9b was more cytotoxic against all four cell lines with IC50 in the range of 0.016 to 0.17 μM. Further 9b is more selective toward A549 and followed by MCF-7. Molecular docking studies of all the target compounds were carried out against hDHFR to see the binding interactions and binding affinities. Ligands 9b and 9c have the highest binding affinities toward hDHFR and these results substantiate the experimental findings. The MEC was analyzed for the most potent compounds 9b and 9c. All the ligands have passed the Insilico ADME properties and haven‘t violated more than one Ro5.

Synthesis, molecular docking, and in vivo antidiabetic evaluation of new benzylidene-2,4-thiazolidinediones as partial PPAR-γ agonists

Peroxisome proliferator-activated receptor-γ (PPAR-γ) partial agonists or antagonists, also termed as selective PPAR-γ modulators, are more beneficial than full agonists because they can avoid the adverse effects associated with PPAR-γ full agonists, such as weight gain and congestive heart disorders, while retaining the antidiabetic efficiency. In this study, we designed and synthesized new benzylidene-thiazolidine-2,4-diones while keeping the acidic thiazolidinedione (TZD) ring at the center, which is in contrast with the typical pharmacophore of PPAR-γ agonists. Five compounds (5a–e) were designed and synthesized in moderate to good yields and were characterized using spectral techniques. The in vivo antidiabetic efficacy of the synthesized compounds was assessed on streptozotocin-induced diabetic mice using standard protocols, and their effect on weight gain was also studied. Molecular docking and molecular dynamics (MD) simulation studies were performed to investigate the binding interactions of the title compounds with the PPAR-γ receptor and to establish their binding mechanism. Antidiabetic activity results revealed that compounds 5d and 5e possess promising antidiabetic activity comparable with the standard drug rosiglitazone. No compound showed considerable effect on the body weight of animals after 21 days of administration, and the findings showed statistical difference (p < 0.05 to p < 0.0001) among the diabetic control and standard drug rosiglitazone groups. In molecular docking study, compounds 5c and 5d exhibited higher binding energies (− 10.1 and − 10.0 kcal/mol, respectively) than the native ligand, non-thiazolidinedione PPAR-γ partial agonist (nTZDpa) (− 9.8 kcal/mol). MD simulation further authenticated the stability of compound 5c-PPAR-γ complex over the 150 ns duration. The RMSD, RMSF, rGyr, SASA, and binding interactions of compound 5c-PPAR-γ complex were comparable to those of native ligand nTZDpa-PPAR-γ complex, suggesting that the title compounds have the potential to be developed as partial PPAR-γ agonists.

Synthesis, in-silico studies, and biological evaluation of some novel 3-thiazolyl-indoles as CDK2–inhibitors

The essential enzyme cyclin-dependent kinase 2 (CDK2) is a promising target for anticancer drug development due to its pivotal role in regulating the cell cycle. This study aimed to synthesize novel 3-thiazolyl-indole derivatives and assess their ability to inhibit CDK2 using molecular docking analyses. A series of these compounds was synthesized through a multistep approach, and various techniques, including NMR, IR, and mass spectrometry, were used for structural characterization. Prolonged molecular dynamics (MD) simulations were conducted to explore pharmacokinetics, toxicity profiles, binding interactions, and structural dynamics. Additionally, nine newly synthesized compounds were evaluated for in vitro cytotoxicity against three human cancer cell lines (HepG2, MCF-7, and HCT-116) in comparison to cisplatin. The results revealed that compounds 5c, 5b, and 10b displayed favorable activities when compared to the reference drug. Furthermore, the inhibitory activity of the most potent compounds (5a-c) was tested in an in vitro enzyme assay against CDK2. The findings indicated that several 3-thiazolyl-indole derivatives exhibited significant inhibitory activity against CDK2, with compound 5c being the most potent (IC50 value of 0.35 ± 1.07 µM compared to roscovitine's 0.39 ± 0.47 µM). Molecular docking revealed the compounds' binding modes in the CDK2 site. This research highlights the potential of 3-thiazolyl-indoles in anticancer drug development.

Synthesis, evaluation of the cytotoxicity, apoptosis induction in AGS cell line and gene expression and molecular modeling studies of novel tetrahydropyrimidine derivatives

Cancer is a complex disease that remains a leading cause of death worldwide owing to the lack of effective and efficient drugs. Compounds known as tetrahydropyrmidine have shown great potential as anti-cancer agents. Here, novel compounds based on tetrahydropyrimidine scaffold were successfully synthesized by the multicomponent reaction of Biginelli reaction. The biological functions of the selected compounds in AGS cells, including cytotoxicity, apoptosis induction, caspase3/7 activity, and gene expressions such as P53, CDNK2A, and Caspase-8/9, were evaluated. All synthesized compounds displayed moderate to good activity against the AGS cell line. Four compounds 4c, 4d, 4i, and 4 m induced apoptosis and activated caspase-3/7. Among them, compound 4c exhibited the highest cytotoxicity (IC50 = 69.60 µM), apoptosis induction, and caspase-3/7 activity. In comparison to other compounds, 4i showed a higher stimulation in the expression of P53, CDNK2A, and Caspase 9 genes. However, even though there was an increasing trend in the genes related to apoptosis and the cell cycle pathways, and the expression of caspase 9 was higher than caspase 8, these differences were not large enough to be significant. In addition, molecular docking studies and MD simulations were carried out to recognize the likely mechanism of the anti-cancer effect. Findings of docking revealed compounds fitted in the active site with good binding. MD simulations showed that compounds 4c, 4d and 4 m made a steady complex with the Eg5 enzyme. Thus, the possible mechanism of anti-cancer activity of these compounds can be through inhibition of the Eg5 enzyme.