Design,synthesis, and evaluation of novel diphenyl ether derivatives against drug‐susceptible and drug‐resistant strains of Mycobacterium tuberculosis

In our efforts to develop druggable diphenyl ethers as potential antitubercular agents, a series of novel diphenyl ether derivatives ( 5a – f , 6a – f ) were designed and synthesized. The representative compounds showed promising in vitro activity against drug‐susceptible, isoniazid‐resistant, and multidrug‐resistant strains of Mycobacterium tuberculosis with MIC values of 1.56 μg/ml ( 6b ), 6.25 μg/ml ( 6a–d ), and 3.125 μg/ml ( 6b–c ), respectively. All the synthesized compounds exhibited satisfactory safety profile (CC₅₀ > 300 μg/ml) against Vero and HepG2 cells. Reverse phase HPLC method was used to probe the physicochemical properties of the synthesized compounds. This series of compounds demonstrated comparatively low logP values. pKa values of representative compounds indicated that they were weak acids. Additionally, in vitro human liver microsomal stability assay confirmed that the synthesized compounds possessed acceptable stability under study conditions. The present study thus establishes compound 6b as the most promising antitubercular agent with acceptable drug‐likeness.     

Graph theoretical analysis,insilico modeling,design, and synthesis of compounds containing benzimidazole skeleton as antidepressant agents

In this study, drug target was identified using KEGG database and network analysis through Cytoscape software. Designed series of novel benzimidazoles were taken along with reference standard Flibanserin for insilico modeling. The novel 4‐(1H‐benzo[d]imidazol‐2‐yl)‐N‐(substituted phenyl)‐4‐oxobutanamide ( 3a–j ) analogs were synthesized and evaluated for their antidepressant activity. Reaction of 4‐(1H‐benzo[d]imidazol‐2‐yl)‐4‐oxobutanoic acid ( 1 ) with 4‐(1H‐benzo [d] imidazol‐2‐yl)‐4‐oxobutanoyl chloride ( 2 ) furnished novel 4‐(1H‐benzo [d] imidazol‐2‐yl)‐N‐(substituted phenyl)‐4‐oxobutanamide ( 3a–j ). All the newly synthesized compounds were characterized by IR, ¹H‐NMR, and mass spectral analysis. The antidepressant activities of synthesized derivatives were compared with standard drug clomipramine at a dose level of 20 mg/kg. Among the derivatives tested, most of the compounds were found to have potent activity against depression. The high level of activity was shown by the compounds 3d , 3e , 3i, and it significantly reduced the duration of immobility time at the dose level of 50 mg/kg.     

Design,Synthesis, and Biological Evaluation of 1,5‐Diaryl‐1,2,4‐triazole Derivatives as Selective Cyclooxygenase‐2 Inhibitors

A series of 1,5‐diaryl‐1,2,4‐triazole derivatives were synthesized and evaluated as cyclooxygenase‐2 (COX‐2) inhibitors. The results of the preliminary biological assays in vivo showed that eight compounds 5b , 6b , 6c , 7c , 8b , 8d , 9c , and 9d have potent anti‐inflammatory activity (P < 0.01), while compounds 6b , 6c , and 9c exhibit marked potency. Compound 6c was then selected for further investigation. In the COX inhibition assay in vitro, compound 6c was identified as a potent and selective inhibitor of COX‐2 (COX‐2 IC₅₀ = 0.37 µM; SI = 0.018), being equipotent to celecoxib (COX‐2 IC₅₀ = 0.26 µM; SI = 0.015). In a rat carrageenan‐induced paw edema assay, 6c exhibited moderate anti‐inflammatory activity (35% inhibition of inflammation) at 2 h after administration of 15 mg/kg as an oral dose. A docking study also revealed that compound 6c binds in the active site of COX‐2 in a similar mode to that of the known selective COX‐2 inhibitor SC‐558.     

Novel 1,3‐oxazine‐tetrazole hybrids as mushroom tyrosinase inhibitors and free radical scavengers: Synthesis,kinetic mechanism,and molecular docking studies

A variety of 5‐(2H‐tetrazol‐5‐yl)‐4‐thioxo‐2‐(substituted phenyl)‐4,5‐dihydro‐1,3‐oxazin‐6‐ones ( 3a–k ) have been synthesized from 1,3‐oxazine‐5‐carbonitriles ( 2a–k ). The protocol represents an efficient, facile, and novel route from easily available precursors to unprecedented structures that share 1,3‐oxazine and tetrazole motifs of utmost value. All the synthesized compounds ( 3a–k ) were evaluated for their inhibitory potential against mushroom tyrosinase. Results revealed that all examined 1,3‐oxazine‐tetrazole hybrids exhibited significant tyrosinase inhibitory activity while compound 3d having 2‐bromophenyl moiety was the most potent among the series with IC₅₀ value 0.0371 ± 0.0018 μM as compared to the reference kojic acid (IC₅₀ = 16.832 ± 0.73 μM). Inhibitory kinetics showed that compound 3d behaves as a competitive inhibitor. The molecular docking analysis was performed against target protein to investigate the binding mode. Moreover, compounds 3j and 3k displayed superior DPPH radical scavenging activity than other analogues.     

Development of novel indole‐linked pyrazoles as anticonvulsant agents: A molecular hybridization approach

A series of 3‐{2‐[1‐acetyl‐5‐(substitutedphenyl)‐4,5‐dihydropyrazol‐3‐yl]hydrazinylidene}‐1,3‐dihydro‐2H‐indol‐2‐ones 24–43 was synthesized using an appropriate synthetic route and evaluated experimentally by the maximal electroshock test. These compounds were evaluated for antidepressant and antianxiety activities. The most active compound, 3‐{2‐[1‐acetyl‐5‐(4‐chlorophenyl)‐4,5‐dihydropyrazol‐3‐yl]hydrazinylidene}‐1,3‐dihydro‐2H‐indol‐2‐one 25 , exhibited an ED₅₀ of 13.19 mmol/kg, a TD₅₀ of 43.49 mmol/kg, and a high protective index of 3.29, compared with the standard drug diazepam. To get insights into the intermolecular interactions, molecular docking studies were performed at the active site of the GABA_A receptor and the MAO‐A enzyme. Molecular docking studies are also in agreement with the pharmacological evaluation with potent compounds, exhibiting docking scores of ?1.5180 and 0.7458 for the GABA_A receptor and MAO‐A, respectively. The 3D‐QSAR analysis was carried out by Vlife MDS engine 4.3.1, and a statistically reliable model with good predictive power (r² = 0.7523, q² = 0.3773) was achieved. The 3D‐QSAR plots gave insights into the structure–activity relationship of these compounds, which may aid in the design of potent benzopyrrole derivatives as anticonvulsant agents. So, our research can make a great impact on those medicinal chemists who work on the development of anticonvulsant agents.     

Synthesis of New Quinoline Derivatives as Inhibitors of Human Tumor Cells Growth

A series of new 8‐[(2H‐tetrazol‐5‐yl)methoxy]quinoline derivatives, their sugar hydrazones, and their N‐glycoside derivatives were synthesized. Furthermore, the 1,2,4‐triazole‐3‐one derivatives 3 and 4 were synthesized from the amidrazone derivative 2 . Some of the newly prepared compounds demonstrated inhibitory effects on the growth of MCF‐7 human breast cancer cells as compared with the activity of the commonly used anticancer drug, cisplatin. The results of antitumor evaluation revealed that compounds 2–5 , 8b , and 12 inhibited the growth of cancer cells through their effect as free‐radical regulators by increasing the activity of superoxide dismutase and depletion of intracellular levels of reduced glutathione, catalase and glutathione peroxidase activities, accompanied with a high production of hydrogen peroxide, nitric oxide, and other free radicals causing the killing of tumor cells. The results suggested that the prepared compounds possess significant anticancer activity comparable to cisplatin and the antitumor activity of these prepared compounds was accompanied with a reduction in the levels of protein and nucleic acids.     

4-substituted 5-[m-(trifluoromethyl)phenoxy]primaquine analogues as potential antimalarial agents

Five 4-substituted 5-[m-(trifluoromethyl)phenoxy]primaquine analogues were synthesized and tested for radical curative activity against Plasmodium cynomolgi in Rhesus monkeys and for blood schizonticidal antimalarial activity against Plasmodium berghei in mice. In addition, they were evaluated for causal prophylactic antimalarial activity against Plasmodium berghei yoelii in mice. One compound, 4-ethyl-5-[m-(trifluoromethyl)phenoxy]primaquine (2b), showed radical curative activity equivalent to 4-methyl-5-[m-(trifluoromethyl)phenoxy]primaquine (2a). A second compound showed radical curative activity slightly less than 2a and 2b; the remaining three compounds were not active against P. cynomolgi. All five compounds showed much higher blood schizonticidal activity and less toxicity than primaquine; however, none of the compounds were as active as 2a. Three of four compounds tested showed high activity against P. berghei yoelii.     

Synthesis of Novel Pyrimidin‐4‐One Bearing Piperazine Ring‐Based Amides as Glycogen Synthase Kinase‐3β Inhibitors with Antidepressant Activity

Novel pyrimidin‐4‐one derivatives have been synthesized using EDC coupling and evaluated as glycogen synthase kinase‐3β (GSK‐3β) inhibitors. Among all the synthesized compounds, compound 5 (3‐methyl‐6‐phenyl‐2‐(piperazin‐1‐yl)‐3,4‐dihydropyrimidin‐4‐one) exhibited the most potent inhibitory activity against GSK‐3β with IC₅₀ value of 74 nm . The molecular docking studies were performed to elucidate the binding modes of the compounds with the target, and a crucial interaction involving hydrogen bond formation with Val‐135 to the active site of GSK‐3β was observed. Furthermore, the synthesized compounds were subjected to in vivo evaluation of their antidepressant activity, and compound 5 showing highest inhibition of GSK‐3β was also found to significantly reduce the duration of immobility at 50 mg/kg, when compared with fluoxetine, a known antidepressant drug. The results of our study suggest that compound 5 may serve as a valuable template for the design and development of inhibitors of GSK‐3β with antidepressant activity.     

Synthesis and Antimicrobial Activity of the Hybrid Molecules between Sulfonamides and Active Antimicrobial Pleuromutilin Derivative

A series of novel hybrid molecules between sulfonamides and active antimicrobial 14‐o‐(3‐carboxy‐phenylsulfide)‐mutilin were synthesized, and their in vitro antibacterial activities were evaluated by the broth microdilution. Results indicated that these compounds displayed potent antimicrobial activities in vitro against various drug‐susceptible and drug‐resistant Gram‐positive bacteria such as Staphylococci and streptococci, including methicillin‐resistant Staphylococcus aureus, and mycoplasma. In particular, sulfapyridine analog ( 6c ) exhibited more potent inhibitory activity against Gram‐positive bacteria and mycoplasma, including Staphylococcus aureus (MIC = 0.016–0.063 μg/mL), methicillin‐resistant Staphylococcus aureus (MIC = 0.016 μg/mL), Streptococcus pneumoniae (MIC = 0.032–0.063 μg/mL), Mycoplasma gallisepticum (MIC = 0.004 μg/mL), with respect to other synthesized compounds and reference drugs sulfonamide (MIC = 8–128 μg/mL) and valnemulin (MIC = 0.004–0.5 μg/mL). Furthermore, comparison between MIC values of pleuromutilin‐sulfonamide hybrids 6a–f with pleuromutilin parent compound 3 revealed that these modifications at 14 position side chain of the pleuromutilin with benzene sulfonamide could greatly improve the antibacterial activity especially against Gram‐positives.     

Synthesis,characterization, and antimicrobial activity of some new N‐aryl‐N’‐(2‐oxoindolin‐3‐ylidene)‐benzohydrazonamides

A green approach was developed for synthesizing a series of (isatin‐3‐ylidene)‐hydrazonamides 3a–j  from the reaction between isatin, (isatin‐3‐ylidene)malononitrile, or 2‐cyano‐2‐(2‐isatin‐3‐ylidene)acetate and benzohydrazonamide in ethyl acetate solutions at ambient temperature. The structures of the new compounds were confirmed on the basis of spectral data. In this eco‐friendly medium, a variety of (isatin‐3‐ylidene)hydrazonamides were obtained free of catalyst in good to excellent yields. All the synthesized products were evaluated for their antimicrobial activity. Among the compounds tested, 3b and 3d exhibited good antibacterial activity against Staphylococcus aureus, whereas others responded moderately with reference to the standard drug ciprofloxacin.     

Design,Synthesis, Biological Evaluation,and Docking Study of Acetylcholinesterase Inhibitors: New Acridone‐1,2,4‐oxadiazole‐1,2,3‐triazole Hybrids

In this study, novel acridone‐1,2,4‐oxadiazole‐1,2,3‐triazole hybrids were designed, synthesized, and evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activity. Among various synthesized compounds, 10‐((1‐((3‐(4‐methoxyphenyl)‐1,2,4‐oxadiazol‐5‐yl)methyl)‐1H‐1,2,3‐triazol‐4‐yl)methyl)acridin‐9(10H)‐one 10b showed the most potent anti‐acetylcholinesterase activity (IC₅₀ = 11.55 μm ) being as potent as rivastigmine. Also docking outcomes were in good agreement with in vitro results confirming the dual binding inhibitory activity of compound 10b .     

New N-phenylacetamide-linked 1,2,3-triazole-tethered coumarin conjugates: Synthesis,bioevaluation, and molecular docking study

A series of new 1,2,3-triazole-tethered coumarin conjugates linked by N-phenylacetamide was efficiently synthesized via the click chemistry approach in excellent yields. The synthesized conjugates were evaluated for their in vitro antifungal and antioxidant activities. Antifungal activity determination was carried out against fungal strains such as Candida albicans, Fusarium oxysporum, Aspergillus flavus, Aspergillus niger and Cryptococcus neoformans. Compounds 7b , 7d , 7e , 8b and 8e displayed higher potency than the standard drug miconazole, with lower minimum inhibitory concentration values. Also, compound 7a exhibited potential radical scavenging activity as compared with the standard antioxidant butylated hydroxytoluene. In addition, a molecular docking study of the newly synthesized compounds was carried out, and the results showed a good binding mode at the active site of the fungal (C. albicans) P450 cytochrome lanosterol 14α-demethylase enzyme. Furthermore, the synthesized compounds were also tested for ADME properties, and they demonstrated potential as good candidates for oral drugs.     

Design,synthesis, and evaluation of a series of novel phenylpropanoic acid derivatives agonists for the FFA1

Free fatty acid 1 (FFA1/GPR40) has attracted extensive attention as a novel target for the treatment of type 2 diabetes for its role in the enhancement of insulin secretion with glucose dependency. Aiming to develop novel potent FFA1 agonists, a new series of phenylpropionic acid derivatives were designed and synthesized on the basis of the modification of chemical cement of TAK‐875, AMG‐837, and LY2881835. Among them, most promising compounds 7 , 14 , and 15 were obtained with EC₅₀ values of 82, 79, and 88 nM, exhibiting a powerful agonistic activity compared to TAK‐875 (95.1 nM). During Oral glucose tolerance test in normal mice, compound 7 , 14 , and 15 had significant glucose‐lowering effect at the dose of 50 mg/kg. Furthermore, compound 15 (50 mg/kg) also significantly improved in glucose tolerance in type 2 diabetic mice. Herein, we reported the discovery and optimization of a series of potent FFA1 agonists. The discovery supported further exploration surrounding this scaffold.     

Synthesis and Biological Evaluation of Strictosamide Derivatives with Improved Antiviral and Antiproliferative Activities

A series of novel derivatives of strictosamide were synthesized and biologically evaluated. Most of the new compounds exhibited improved activities than the parent compound strictosamide. Among them, compounds Ib and If possessed antiviral activities against influenza A virus (A/Jinan/15/90) with IC₅₀ values of 4.12 and 12.35 μg/mL, respectively. Compound Ie possessed antiviral activity against respiratory syncytial virus (RSV) with an IC₅₀ value of 9.58 μg/mL. Both compounds IIc and IId had moderate antiproliferative effects against five human cancer cell lines. The preliminary structure‐activity relationships were also concluded. This study provides a promising new template with potential antiviral activity.     

Synthesis,biological evaluation,and docking studies of some 5‐chloro‐2(3H)‐benzoxazolone Mannich bases derivatives as cholinesterase inhibitors

A series of N‐substituted‐5‐chloro‐2(3H)‐benzoxazolone derivatives were synthesized and evaluated for their acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) inhibitory, and antioxidant activities. The structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman's colorimetric method. The free radical scavenging activity was also determined by in vitro ABTS (2,2‐azinobis(3‐ethylbenzothiazoline‐6‐sulfonic acid)) assay. The biological activity results revealed that all of the title compounds displayed higher AChE inhibitory activity than the reference compound, rivastigmine, and were selective for AChE. Among the tested compounds, compound 7 exhibited the highest inhibition against AChE (IC₅₀ = 7.53 ± 0.17 μM), while compound 11 was found to be the most active compound against BuChE (IC₅₀ = 17.50 ± 0.29 μM). The molecular docking study of compound 7 showed that this compound can interact with the catalytic active site (CAS) of AChE and also has potential metal chelating ability and a proper log P value. On the other hand, compound 2 bearing a methyl substituent at the ortho position on the phenyl ring showed better radical scavenging activity (IC₅₀ = 1.04 ± 0.04 mM) than Trolox (IC₅₀ = 1.50 ± 0.05 mM).

     

In vivo antihyperlipidemic activity of a new series of N-(benzoylphenyl) and N-(acetylphenyl)-1-benzofuran-2-carboxamides in rats

A new series of N‐(benzoylphenyl) and N‐(acetylphenyl)‐1‐benzofuran‐2‐carboxamides ( 3a – 3d and 4a ′– 4c ′) were synthesized. Compounds ( 3a , 3b , and 4a ′– 4c ′) were tested in vivo using Triton‐WR‐1339‐induced hyperlipidemic rats as an experimental model for their hypolipidemic activity. The tested animals were divided into eight groups: control, hyperlipidemic, 3a , 3b , 4a ′, 4b ′, 4c ′, and bezafibrate. At a dose of 15 mg/kg, the elevated plasma triglyceride (TG) levels were significantly reduced in compounds 3b (p <0.0001) and 4c ′ (p <0.05) after 12 and 24 h compared to the normal control group. Furthermore, high‐density lipoprotein‐cholesterol levels were remarkably increased in compounds 3b (p <0.001) and 4c ′ (p <0.05). Meanwhile, compound 4b ′ slightly reduced the TG levels after 12 and 24 h. The present study demonstrated new properties of the novel series of benzofuran‐2‐carboxamides 3b and 4c ′ as potent lipid‐lowering agents. It is, therefore, reasonable to assume that compounds 3b and 4c ′ may have a promising potential in the treatment of hyperlipidemia and coronary heart diseases.