Design,synthesis, biological evaluation,and molecular modeling studies of rhodanine derivatives as pancreatic lipase inhibitors

A series of rhodanine‐3‐acetic acid derivatives were synthesized via Knoevenagel condensation of rhodanine‐3‐acetic acid with various substituted aromatic aldehydes. The synthesized derivatives were screened in vitro for understanding the inhibitory potential towards pancreatic lipase (PL), a key enzyme responsible for the digestion of dietary fats. Derivative 8f exhibited a potential inhibitory activity towards PL (IC₅₀ = 5.16 µM), comparable to that of the standard drug, orlistat (0.99 µM). An increase in the density of the aromatic ring resulted in potential PL inhibition. The enzyme kinetics of 8f exhibited a reversible competitive‐type inhibition, similar to that of orlistat. Derivative 8f exhibited a MolDock score of ‐125.19 kcal/mol in docking studies, and the results were in accordance with their PL inhibitory potential. Furthermore, the reactive carbonyl group of 8f existed at a distance adjacent to Ser152 (≈3 Å) similar to that of orlistat. Molecular dynamics simulation (10 ns) of the 8f ‐PL complex revealed a stable binding conformation of 8f in the active site of PL (maximum root mean square displacement of ≈2.25 Å). The present study identified novel rhodanine‐3‐acetic acid derivatives with promising PL inhibitory potential, and further lead optimization might result in potent PL inhibitors.     

Design,synthesis, and molecular docking of novel 2-arylbenzothiazole multiangiokinase inhibitors targeting breast cancer

A novel series of 2-arylbenzothiazoles 9, 10 , and 12 were designed and synthesized as VEGFR-2/FGFR-1/PDGFR-β multiangiokinase inhibitors targeting breast cancer. Structural elongation of the known 2-phenylbenzothiazole scaffold (type I protein kinase inhibitor [PKI]), was carried out to afford series of type II PKIs 9, 10 , and 12 . Compounds 9d, 9f, 9i , and 9k exhibited potent multikinase inhibitory activity with IC₅₀ values of 0.19, 0.18, 0.17, and 0.13 μM, respectively, against VEGFR-2; IC₅₀ values of 0.28, 0.37, 0.19, and 0.27 μM, respectively, against FGFR-1; and IC₅₀ values of 0.07, 0.04, 0.08, and 0.14 μM, respectively, against PDGFR-β. Moreover, the synthesized benzothiazoles demonstrated promising cytotoxic activity against the MCF-7 cell line. The most potent benzothiazoles 9d and 9i exhibited IC₅₀ values of 7.83 and 6.58 μM, respectively, on the MCF-7 cell line in comparison to sorafenib ( III ), which showed IC₅₀ = 4.33 μM. Additionally, 9d and 9i showed VEGFR-2 inhibitory activity in MCF-7 cells of 81% and 83% when compared with sorafenib ( III ), which showed 88% inhibition. Molecular docking of the designed compounds in the VEGFR-2 and FGFR-1 active sites showed the accommodation of the 2-phenylbenzothiazole moiety, as reported, in the hinge region of the receptor tyrosine kinase (RTK)-binding site, while the amide moiety is involved in hydrogen bond interactions with the key amino acids in the gate area; this in turn directs the aryl group to the hydrophobic allosteric back pocket of the RTKs in a type II-like binding mode. The synthesized benzothiazoles showed satisfactory ADME properties for further optimization in drug discovery.     

Synthesis,in silico and in vitro studies of hydrazide-hydrazone imine derivatives as potential cholinesterase inhibitors

A series of hydrazide-hydrazone imine derivative compounds (3a–k) were synthesized and their structures characterized using FTIR, ¹H, and ¹³C (NMR) spectroscopic methods. In addition, molecular structures of compounds 3a, 3d, and 3g were elucidated by X-ray diffraction technique. In vitro inhibition activities of hydrazide-hydrazone imine derivatives against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were investigated. Compound 3i (IC₅₀ = 2.01 μM) exhibited the best inhibitory activity against AChE, comparable to the control Galantamine (IC₅₀ = 2.60 μM). Against BChE, compound 3h (IC₅₀ = 2.83 μM) showed the best inhibitory property which is higher control Galantamine (IC₅₀ = 3.70 μM). The Ki values of compound 3i (Ki = 0.63 μM) and compound 3h (Ki = 0.94 μM) that have the strongest inhibitory potential were determined against AChE and BChE, respectively. According to the docking result, the most stable conformation of AChE and compound 3i showed that it has a binding affinity of −10.82 kcal/moL. The binding affinity of the most stable conformation formed by BChE and compound 3h is −8.60 kcal/moL. Finally, in silico results and pharmacokinetic parameters of ADME showed that these compounds have good oral bioavailability properties.     

Evaluation of selected commercial pharmacotherapeutic drugs as potential pancreatic lipase inhibitors and antiproliferative compounds

In this study, 15 commercial acidic drugs have been evaluated for pancreatic lipase (PL) inhibitory activity using an in vitro spectrophotometric method. The acidity was the basis of selection, since most PL inhibitors exhibit acidic groups and high lipophilicity. Orlistat was the robust reference agent for potency and efficacy determinations. In comparison to the cisplatin, the evaluation of the antineoplastic activities of selected drugs in a panel of colorectal cancer cell lines (HT-29, HCT-116, SW620, CACO-2, and SW480) and normal periodontal ligament fibroblasts for safety examination was performed by using a sulforhodamine procuring ascorbic acid as a reference in diphenyl-2-picryl-hydrazyl assay of radical scavenging properties was performed. This research revealed three highly acidic pharmacological classes with reasonable PL inhibitory activity in comparison to orlistat out of 15 selected drugs, namely sulfonylureas, fluoroquinolones, and proton pump inhibitors. Docking studies supported the hypothesis of a selection based on acidity, since it showed that the sulfonamide acid group (glyburide) is a remarkably potent interacting group with the enzyme. Failing to fulfill other structure-activity relationship requirements (lipophilicity) led to weak activity. Since the drugs are of different chemical classes with unknown mechanisms, they showed diverse antiproliferative activity. Some drugs such as atorvastatin and gemifloxacin showed higher antiproliferative activity than cisplatin with high-safety profiles against SW620 and SW480 cell lines, respectively, whereas lansoprazole and clopidogrel revealed comparable activity to cisplatin against HCT-116 and SW480, respectively. Unfortunately, selected tested drugs exhibited negligible radical scavenging activity versus ascorbic acid.

Design and synthesis of Atglistatin derivatives as adipose triglyceride lipase inhibitors

Adipose triglyceride lipase (ATGL) is a rate‐limiting enzyme that mobilizes fatty acids from cellular triglyceride stores. Metabolic syndrome, which refers to a group of abnormalities that occur together and increase the risk of coronary artery disease, stroke, type 2 diabetes, and cachexia, can be treated using ATGL‐specific inhibitors. Atglistatin ( 1 ) is the first small‐molecule inhibitor of ATGL. In this study, we designed and synthesized 29 Atglistatin derivatives and evaluated their inhibition of forskolin‐stimulated lipolysis in 3T3‐L1 adipocytes as an indicator of their potential to inhibit ATGL in adipose tissues. Among all the tested Atglistatin analogs, we previously found that the thiourea compound 9e showed potent ATGL inhibitory activity in vitro, which was much stronger than that of Atglistatin, and its inhibitory activity in vivo was similar to that of Atglistatin. This tool compound could be used to study the pathophysiology and druggability of ATGL in animal models of metabolic disease and cachexia.     

Design,synthesis, biological evaluation,and molecular dynamics of novel cholinesterase inhibitors as anti‐Alzheimer's agents

A series of novel chroman‐4‐one derivatives were designed and synthesized successfully with good to excellent yield ( 3a–l ). In addition, the obtained products were evaluated for their cholinesterase (ChE) inhibitory activities. The results show that among the various synthesized compounds, analogs bearing the piperidinyl ethoxy side chain with 4‐hydroxybenzylidene on the 3‐positions of chroman‐4‐one ( 3l ) showed the most potent activity with respect to acetylcholinesterase (anti‐AChE activity; IC₅₀ = 1.18 μM). In addition, the structure–activity relationship was studied and the results revealed that the electron‐donating groups on the aryl ring of the 3‐benzylidene fragment ( 3k , 3l ) resulted in the designed compounds to be more potent ChE inhibitors in comparison with those having electron‐withdrawing groups ( 3h ). In this category, the strongest ChE inhibition was found for the compound containing piperidine as cyclic amine, and a hydroxyl group (for AChE, compound 3l ) and fluoro group (for butyrylcholinesterase (BuChE, compound 3i ) on the para‐position of the aryl ring of the benzylidene group. The molecular docking and dynamics studies of the most potent compounds ( 3i and 3l against BuChE and AChE, respectively) demonstrated remarkable interactions with the binding pockets of the ChE enzymes and confirmed the results obtained through in vitro experiments.     

Densely substituted piperidines as a new class of elastase inhibitors: Synthesis and molecular modeling studies

Elastase is the only enzyme that has the capability to degrade elastin and collagen, the two proteins essential for skin and bones. The synthesis of some densely substituted piperidines functionalized with the trifluoromethyl group ( 4a‐j ) was carried out. The newly prepared compounds were subjected to elastase enzyme inhibitory potential and antioxidant activity assays. Among the series, 4i (IC₅₀ = 0.341 ± 0.001 μM) exhibited the maximum inhibition against elastase. Binding analysis delineated that the fluorine atom of ligand 4i showed hydrogen and hydrophobic bonds with Thr41 and Thr96, with bond distances of 3.84 and 5.631 Å, respectively. The obtained results indicate that these trifluoromethyl functionalized piperidine derivatives could be considered as potential candidates to treat skin disorders.     

Design,microwave‐assisted synthesis,biological evaluation and molecular modeling studies of 4‐phenylthiazoles as potent fatty acid amide hydrolase inhibitors

Endocannabinoids, anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG), are endogenous lipids that activate cannabinoid receptors. Activation of these receptors produces anti‐inflammatory and analgesic effects. Fatty acid amide hydrolase (FAAH) is a membrane enzyme that hydrolases endocannabinoids; thus, inhibition of FAAH represents an attractive approach to develop new therapeutics for treating inflammation and pain. Previously, potent rat FAAH inhibitors containing 2‐naphthyl‐ and 4‐phenylthiazole scaffolds were identified, but up to the present time, very little structure–activity relationship studies have been performed on these moieties. We designed and synthesized several analogs containing these structural motifs and evaluated their inhibition potencies against human FAAH enzyme. In addition, we built and validated a homology model of human FAAH enzyme and performed docking experiments. We identified several inhibitors in the low nanomolar range and calculated their ADME predicted values. These FAAH inhibitors represent promising drug candidates for future preclinical in vivo studies.     

Design, synthesis, molecular modeling, and biological evaluation of sulfanilamide-imines derivatives as potential anticancer agents

A series of sulfanilamide Schiff base derivatives (1 to 15) have been designed as potential antitubulin agents depending on the chemical structures of combretastatine A-4 and isoquinoline sulfamate (antimitotic agents under investigation). The designed compounds were synthesized by microwave chemical synthesis, their purity was confirmed by melting point and HPLC and chemical structures were determined by FT-IR, UV, and ¹H and ¹³C-NMR spectroscopic techniques. The synthesized compounds have been docked in the colchicine binding site of β-tubulin using molecular modeling programs and the antitumor activities were screened on human breast and lung cancer cells by cell counting assay. Some tested compounds showed potent and selective activity against breast cancer (MCF-7) with IC₅₀ range of 90 to 166 μM. With regarding broad-spectrum activity, compounds 4, 8, and 13 have shown potent antitumor activity against human breast and human lung cells with IC₅₀ range of 96 to 140 μM. The obtained results suggest that the sulfanilamide Schiff base derivatives might potentially constitute an interesting novel class of anticancer agents, which deserve further studies.     

Synthesis,molecular modeling studies,ADME prediction of arachidonic acid carbamate derivatives,and evaluation of their acetylcholinesterase activity

In this work, a series of novel anandamide units containing carbamate were designed and synthesized. All the derivatives were evaluated in vitro for their inhibitory potential against the electric eel acetylcholinesterase enzyme (AChE) and showed reversible inhibitions. The compounds 7a , 7d , 7e , and 7f are mixed inhibitors of AChE, while the compounds 7b , 7c , and 7g are uncompetitive (K_i in the range 0.93–8.86 μM). The kinetic studies revealed that compounds 7b , 7c , 7f , and 7g inhibit considerably AChE activity. Molecular docking analyses were made to evaluate the binding type and interactions of the synthesized compounds to the ligand-binding site of hAChE. It was observed that the docking results were in parallel with the in vitro results. The adsorption, distribution, metabolism, and excretion properties were computed for the compounds, and were found within the acceptable range. This study suggests the compounds 7b , 7c , 7f , and 7g identified as novel reversible AChE inhibitors may be useful lead compounds for the treatment of Alzheimer's disease.     

New quinazolinone-based derivatives as DHFR/EGFR-TK inhibitors: Synthesis,molecular modeling simulations,and anticancer activity

New 2-mercapto-quinazolin-4-one analogs were synthesized and tested for their in vitro anticancer activity, dihydrofolate reductase (DHFR) inhibition, and epidermal growth factor tyrosine kinase (EGFR-TK) inhibition activities. Compound 24 , which is characterized by a 2-benzyl-thio function, showed broad-spectrum anticancer activity with high safety profile and selectivity index. The concentrations of 24 causing 50% growth inhibition (GI₅₀) and total cell growth inhibition (TGI) and its lethal concentration 50 (LC₅₀) were 15.1, 52.5, and 91.2 µM, respectively, using 5-fluorouracil as a positive control. Also, it showed EGFR-TK inhibitory activity with IC₅₀ = 13.40 nM compared to gefitinib (IC₅₀ = 18.14 nM) and DHFR inhibitory potency with 0.30 μM compared to methotrexate (MTX; IC₅₀ = 0.08 μM). In addition, compound 24 caused cell cycle arrest and apoptosis on COLO-205 colon cancer cells. Compounds 37, 21 , and 54 showed remarkable DHFR inhibitory activity with IC₅₀ values of 0.03, 0.08, and 0.08 μM, respectively. The inhibitory properties of these compounds are due to an electron-withdrawing group on the quinazolinone ring, except for compound 54 . In a molecular modeling study, compound 24 showed the same binding mode as gefitinib as it interacted with the amino acid Lys745 via π–π interaction. Compound 37 showed a similar binding mode as MTX through the binding interaction with Lys68, Asn64 via hydrogen bond acceptor, and Phe31 via arene–arene interaction. The obtained model and substitution pattern could be used for further development.     

Design,synthesis, biological evaluation,and molecular docking of novel flavones as H3R inhibitors

A series of novel flavone derivatives were designed, synthesized, and evaluated for their H₃R inhibitory activity. The results showed that four compounds exhibited significant anti‐H₃R activity. Molecular docking experiments indicated that a salt bridge, hydrogen‐bonding, and hydrophobic interactions all contributed to interactions between inhibitors and H₃R.     

Pharmacophore modeling, 3D-QSAR studies, and in-silico ADME prediction of pyrrolidine derivatives as neuraminidase inhibitors

Neuraminidase (NA) is a major glycoprotein of influenza virus which is essential for viral infection. It offers a potential target for antiviral drug development. To develop potent NA inhibitors, pharmacophore models were generated by genetic algorithm with linear assignment for hypermolecular alignment of data sets. 3D-QSAR studies were carried out on 49 molecules. Both comparative molecular field analysis (q(2) = 0.720 and r(2) = 0.947) and comparative molecular similarity indices analysis (q(2) = 0.644 and r(2) = 0.885) yielded reasonable results. A preliminary pharmacokinetic profile of these neuraminidase inhibitors was predicted using Volsurf module.     

Design,synthesis, molecular modeling,and antimicrobial potential of novel 3-[(1H-pyrazol-3-yl)imino]indolin-2-one derivatives as DNA gyrase inhibitors

A series of 3-[(1H-pyrazol-3-yl)imino]indolin-2-one derivatives were designed using the molecular hybridization method, characterized using different spectroscopic techniques, and evaluated for their in vitro antimicrobial activity. Most of the target compounds demonstrated good to moderate antimicrobial activity compared with ciprofloxacin and fluconazole. Four compounds ( 8b , 9a , 9c , and 10a ) showed encouraging results, with minimal inhibitory concentration (MIC) values (53.45–258.32 µM) comparable to those of norfloxacin (100.31–200.63 µM) and ciprofloxacin (48.33–96.68 µM). Noticeably, the four derivatives revealed excellent bactericidal and fungicidal activities, except for the bacteriostatic potential of compounds 8b and 9a against Escherichia coli and Staphylococcus aureus, respectively. The time-killing kinetic study against S. aureus confirmed the efficacy of these derivatives. Furthermore, two of the four promising derivatives, 9a and 10a , could prevent the formation of biofilms of S. aureus without affecting the bacterial growth at low concentrations. A combination study with seven commercial antibiotics against the multidrug-resistant bacterium P. aeruginosa showed a notable reduction in the antibiotic MIC values, represented mainly through a synergistic or additive effect. The enzymatic assay implied that the most active derivatives had inhibition potency against DNA gyrase comparable to that of ciprofloxacin. Molecular docking and density functional theory calculations were performed to explore the binding mode and study the reactivity of the promising compounds.     

Xanthones as potential α-glucosidase non-competition inhibitors: Synthesis,inhibitory activities,and in silico studies

α-glucosidase inhibitors (AGIs) were commonly used in clinical for the treatment of type 2 diabetes. Xanthones were naturally occurring antioxidants, and they may also be potential AGIs. In this study, eleven 1,6- and 1,3-substituted xanthone compounds were designed and synthesized, of which four were new compounds. Their α-glucosidase inhibitory activities in vitro and in silico were evaluated. Five xanthone compounds with higher activity than acarbose were screened out, and the xanthones substituted at the 1,6-positions were more likely to be potential α-glucosidase non-competitive inhibitors. The binding mode of xanthones with α-glucosidase was further studied by molecular docking method, and the results showed that the inhibitory effect of non-competitive inhibitors on site 1 of α-glucosidase may be related to the hydrogen bonds formed by the compounds with amino acid residues ASN165, HIS209, TRY207, ASP243, and SER104. This study provided a theoretical basis of the rapid discovery and structural modification of non-competitive xanthone inhibitors of α-glucosidase.     

Design,synthesis, and molecular modeling of heterocyclic bioisostere as potent PDE4 inhibitors

A new hybrid template was designed by combining the structural features of phosphodiesterase 4 (PDE4) inhibitors with several heterocyclic moieties which present an integral part in the skeleton of many apoptotic agents. Thirteen compounds of the synthesized hybrids displayed higher inhibitory activity against PDE4B than the reference drug, roflumilast. Further investigation indicated that compounds 13b and 20 arrested the cell cycle at the G2/M phase and the pre‐G1 phase, and induced cell death by apoptosis of A549 cells in a caspase‐dependent manner.

     

Synthesis,evaluation, molecular docking,and molecular dynamics studies of novel N-(4-[pyridin-2-yloxy]benzyl)arylamine derivatives as potential antitubercular agents

A new series of novel triclosan (2,4,4′-trichloro-2′-hydroxydiphenylether) analogues were designed, synthesized, and screened for their in vitro antimycobacterial and antibacterial activities. Most of the compounds showed significant activity against Mycobacterium tuberculosis H37Rv strain with minimum inhibitory concentration (MIC) values in 20–40 μM range in GAST/Fe medium when compared with triclosan (43 μM) in the first week of assay, and after additional incubation, seven compounds, that is, 2a , 2c , 2g , 2h , 2i , 2j , and 2m , exhibited MIC values at the concentration of 20–40 μM. The compounds also showed more significant activity against Bacillus subtilis and Staphylococcus aureus. The synthesized compounds showed druggable properties, and the predicted ADME (absorption, distribution, metabolism, and excretion) properties were within the acceptable limits. The in silico studies predicted better interactions of compounds with target protein residues and a higher dock score in comparison with triclosan. Molecular dynamics simulation study of the most active compound 2i was performed in order to further explore the stability of the protein–ligand complex and the protein–ligand interaction in detail.     

Molecular modeling, synthesis, and preliminary biological evaluation of glutathione-S-transferase inhibitors as potential therapeutic agents

Changes in the GSH/GST system have been found to correlate with resistance to anticancer alkylating agents, presumably through accelerated detoxification of these drugs since some GSTs have been shown to catalyze the conjugation of GSH to specific antineoplastic agents. GSH-alkyl derivatives were designed by molecular modeling, synthesized, and tested as inhibitors of human GST-Pi.     

Design,synthesis, and biological evaluation of chrysin derivatives as potential FabH inhibitors

New series of chrysin derivatives ( 4a – 4t ) were designed and synthesized by introducing different substituted piperazines at C‐7 position. Their inhibitory effects on FabH were evaluated using two Gram‐negative bacterial strains, Escherichia coli and Pseudomonas aeruginosa, and two Gram‐positive bacterial strains, Bacillus subtilis and Staphylococcus aureus. To our delight, most of these compounds exhibited a dramatic increase in inhibitory potency, compared with the control positive drugs. Among them, compound 4s exhibited the most potent inhibitory activity with IC₅₀ values of 5.78 ± 0.24 μm inhibiting E. coli FabH and potent antibacterial activity against S. aureus and E. coli with MIC of 1.25 ± 0.01, 1.15 ± 0.12 μg/mL, respectively, comparing to the control positive drugs penicillin G (7.56 ± 0.30 μm ). Docking simulation was performed to position compound 4s into the FabH active site, and the result showed that compound 4s could bind well with the FabH as potent FabH inhibitor.     

Combined comparative molecular field analysis,comparative molecular similarity indices analysis,molecular docking and molecular dynamics studies of histone deacetylase 6 inhibitors

Human histone deacetylase isoform 6 (HDAC6) has been shown to have an immense role in cell motility and aggresome formation and is being an attractive selective target for the treatment of multiple tumour types and neurodegenerative conditions. The discovery of selective HDAC6 inhibitors with new chemical functionalities is therefore of utmost interest to researchers. In order to examine the structural requirements for HDAC6‐specific inhibitors and to derive predictive model which can be used for designing new selective HDAC6 inhibitors, a three‐dimensional quantitative structure–activity relationship study was carried out on a diverse set of ligands using common feature‐based pharmacophore alignment followed by employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. The models displayed high correlation of 0.978 and 0.991 for best CoMFA and CoMSIA models, respectively, and a good statistical significance. The model could be used for predicting activities of the test set compounds as well as for deriving useful information regarding steric, electrostatic, hydrophobic properties of the molecules used in this study. Further, the training and test set molecules were docked into the HDAC6 binding site and molecular dynamics was carried out to suggest structural requirements for design of new inhibitors.