Design,Synthesis, and Biological Evaluation of 1‐(thiophen‐2‐yl)‐9H‐pyrido[3,4‐b]indole Derivatives as Anti‐HIV‐1 Agents

A novel series of 1‐(thiophen‐2‐yl)‐9H‐pyrido [3,4‐b]indole derivatives were synthesized using DL‐tryptophan as starting material. All the compounds were characterized by spectral analysis such as ¹H NMR, Mass, IR, elemental analysis and evaluated for inhibitory potency against HIV‐1 replication. Among the reported analogues, compound 7g exhibited significant anti‐HIV activity with EC₅₀ 0.53 μm and selectivity index 483; compounds 7e , 7i , and 7o displayed moderate activity with EC₅₀ 3.8, 3.8, and 2.8 μm and selectivity index >105, >105, and 3.85, respectively. Interestingly, compound 7g inhibited p24 antigen expression in acute HIV‐1_IIIB infected cell line C8166 with EC₅₀ 1.1 μm . In this study, we also reported the Lipinski rule of 5 parameters, predicted toxicity profile, drug‐likeness, and drug score of the synthesized analogues.     

Some Hydrazones of 2‐Aroylamino‐3‐methylbutanohydrazide: Synthesis,Molecular Modeling Studies,and Identification as Stereoselective Inhibitors of HIV‐1

In accordance with our antiviral drug development attempt, acylhydrazone derivatives bearing amino acid side chains were synthesized for the evaluation of their antiviral activity against various types of viruses. Among these compounds, 8 _S , 11 _S , and 12 _S showed anti‐HIV‐1 activity with a 50% inhibitory concentration (IC₅₀) = 123.8 µM (selectivity index, SI > 3), IC₅₀ = 12.1 µM (SI > 29), IC₅₀ = 17.4 µM (SI > 19), respectively. Enantiomers 8 _R , 11 _R , and 12 _R were inactive against the HIV‐1 strain III_B. Hydrazones 8 _S , 11 _S , and 12 _S which were active against HIV‐1 wild type showed no inhibition against a double mutant NNRTI‐resistant strain (K103N;Y181C). Molecular docking calculations of R‐ and S‐enantiomers of 8 , 11 , and 12 were performed using the hydrazone‐bound novel site of HIV‐1 RT.     

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 .     

Synthesis and Biological Evaluation of a Series of 2‐((1‐substituted‐1H‐1,2,3‐triazol‐4‐yl)methylthio)‐6‐(naphthalen‐1‐ylmethyl)pyrimidin‐4(3H)‐one As Potential HIV‐1 Inhibitors

A series of novel S‐DABO derivatives with the substituted 1,2,3‐triazole moiety on the C‐2 side chain were synthesized using the simple and efficient CuAAC reaction, and biologically evaluated as inhibitors of HIV‐1. Among them, the most active HIV‐1 inhibitor was compound 4‐((4‐((4‐(2,6‐dichlorobenzyl)‐5‐methyl‐6‐oxo‐1,6‐dihydropyrimidin‐2‐ylthio)methyl)‐1H‐1,2,3‐triazol‐1‐yl)methyl)benzenesulfonamide ( B5b7) , which exhibited similar HIV‐1 inhibitory potency (EC₅₀ = 3.22 μm ) compared with 3TC (EC₅₀ = 2.24 μm ). None of these compounds demonstrated inhibition against HIV‐2 replication. The preliminary structure–activity relationship (SAR) of these new derivatives was discussed briefly.     

Synthesis,molecular docking,and pharmacological evaluation of N‐(2‐(3,5‐dimethoxyphenyl)benzoxazole‐5‐yl)benzamide derivatives as selective COX‐2 inhibitors and anti‐inflammatory agents

A series of N‐(2‐(3,5‐dimethoxyphenyl)benzoxazole‐5‐yl)benzamide derivatives ( 3am ) was synthesized and evaluated for their in vitro inhibitory activity against COX‐1 and COX‐2. The compounds with considerable in vitro activity (IC₅₀ < 1 μM) were evaluated in vivo for their anti‐inflammatory potential by the carrageenan‐induced rat paw edema method. Out of 13 newly synthesized compounds, 3a , 3b , 3d , 3g , 3j , and 3k were found to be the most potent COX‐2 inhibitors in the in vitro enzymatic assay, with IC₅₀ values in the range of 0.06–0.71 μM. The in vivo anti‐inflammatory activity of these six compounds ( 3a , 3b , 3d , 3g , 3j , and 3k ) was assessed by the carrageenan‐induced rat paw edema method. Compounds 3d (84.09%), 3g (79.54%), and 3a (70.45%) demonstrated significant anti‐inflammatory activity compared to the standard drug ibuprofen (65.90%) and were also found to be safer than ibuprofen, by ulcerogenic studies. A docking study was done using the crystal structure of human COX‐2, to understand the binding mechanism of these inhibitors to the active site of COX‐2.

     

Synthesis,Biological Evaluation,and Molecular Docking of 8‐imino‐2‐oxo‐2H,8H‐pyrano[2,3‐f]chromene Analogs: New Dual AChE Inhibitors as Potential Drugs for the Treatment of Alzheimer's Disease

Alzheimer's disease onset and progression are associated with the dysregulation of multiple and complex physiological processes, and a successful therapeutic approach should therefore address more than one target. In line with this modern paradigm, a series of 8‐imino‐2‐oxo‐2H,8H‐pyrano[2,3‐f]chromene analogs ( 4a – q ) were synthesized and evaluated for their multitarget‐directed activity on acetylcholinesterase, butyrylcholinesterase (BuChE), 2,2’‐azino‐bis(3‐ethylbenzthiazoline‐6‐sulfonic acid) (ABTS) radical, and amyloid‐β peptide (Aβ) specific targets for Alzheimer's disease therapy. Most of the synthesized compounds showed remarkable acetylcholinesterase inhibitory activities in low nm concentrations and good ABTS radical scavenging activity, however, no evidence of BuChE inhibitory activity. Among them, 3‐bromobenzylamide derivative 4m exhibited the best acetylcholinesterase inhibitory activity with IC₅₀ value of 13 ± 1.4 nm which is 51‐fold superior to galantamine, a reference drug. Kinetic and molecular docking studies indicated 4m as mixed‐type inhibitor, binding simultaneously to catalytic active and peripheral anionic sites of acetylcholinesterase. Five compounds 4e , 4f , 4g , 4j , and 4k have shown 1.4‐ to 2.5‐fold of higher antioxidant activities than trolox. Interestingly, the most active compound 4m demonstrated dosage‐dependent acceleration of Aβ_1?42 aggregation, which may reduce toxicity of oligomers. Overall, these results lead to discovery of fused tricyclic coumarins as promising dual binding site inhibitors of acetylcholinesterase and afford multifunctional compounds with potential impact for further pharmacological development in Alzheimer's therapy.     

Amino Acid Derivatives,Part 4: Synthesis and Anti‐HIV Activity of New Naphthalene Derivatives

A new series of 2‐(naphthalen‐2‐yloxy)‐N‐[(aryl‐5‐thioxo‐4,5‐dihydro‐1H‐1,2,4‐triazol‐3‐yl)methyl] acetamides 5a–f was synthesized from naphthalene‐derived glycine derivative 2 via the hydrazinoacetamide analogs 4a–f . Alternatively, treatment of 4a with H₂SO₄ afforded 2‐(naphthalen‐2‐yloxy)‐N‐((5‐(phenylamino)‐1,3,4‐thiadiazol‐2‐yl)methyl) acetamide 6a . Alkylation or sulphonylation of 5a afforded the S‐alkylated derivatives 7 and 8 , respectively. Interestingly, treatment of 3 with methoxide ion gave the triazine derivative 9 . The synthesized compounds have been screened for their inhibitory activity against HIV‐1 and HIV‐2 in MT‐4 cells. However, 7 was found to be the potent inhibitor in vitro for the replication of HIV‐1 (EC₅₀ = 0.20 μg/mL), suggesting a new lead in the development of an antiviral agent.     

Synthesis and Antifungal Activity of 1‐Aryl‐3‐phenethylamino‐1‐propanone Hydrochlorides and 3‐Aroyl‐4‐aryl‐1‐phenethyl‐4‐piperidinols

Mono‐Mannich bases, 1‐aryl‐3‐phenethylamino‐1‐propanone hydrochlorides, 1a, 2a , 3a , 4a , 5a , 6a , 7a , 8a , 9a , and semi‐cyclic mono‐Mannich bases, 3‐aroyl‐4‐aryl‐1‐phenethyl‐4‐piperidinols, 1b , 2b , 3b , 4b , 5b , 6b , 7b , 8b , 9b , were synthesized by a non‐classical Mannich reaction. The aryl part was: C₆H₅ for 1a , 1b ; 4‐CH₃C₆H₄ for 2a , 2b ; 4‐CH₃OC₆H₄ for 3a , 3b ; 4‐ClC₆H₄ for 4a , 4b ; 4‐FC₆H₄ for 5a , 5b ; 4‐BrC₆H₄ for 6a , 6b ; 2,4‐(Cl)₂C₆H₃ for 7a , 7b ; 4‐NO₂C₆H₄ for 8a , 8b ; and C₄H₃S(2‐yl) i. e., 2‐thienyl for 9a , 9b . Piperidinol compounds 2b , 3b , 4b , 5b , 7b , 8b , and 9b are reported here for the first time. The synthesized compounds were tested against seven types of plant pathogenic fungi and three types of human pathogenic fungi using the agar dilution assay. Itraconazole was tested against Candida parapsilosis as the reference compound, while Nystatin was tested as the reference compound against the other fungi. Compounds 1a , 1b , 2a , 4a , 4b , 5a , 5b , 6a , 7a , 8a , 9a , and 9b can be selected as model compounds to develop new antifungal agents against the human pathogen Microsporum canis. Compounds 8a and 8b , which had a similar antifungal activity compared with the reference compound Nystatin against the plant pathogen Aspergillus flavus, can serve as model compounds to develop new antifungal agents to solve agricultural problems.     

Synthesis and pp60c‐Src Tyrosine Kinase Inhibitory Activities of Novel Indole‐3‐Imine and Amine Derivatives Substituted at N1 and C5

A series of novel 1,3,5‐trisubstituted indole derivatives, namely, N‐benzyl 5‐phenyl indole‐3‐imine, N‐benzyl‐5‐(p‐fluorophenyl)indole‐3‐imine and their corresponding amine congeners, were designed and synthesized as pp60^c‐Src tyrosine kinase inhibitors, and their inhibitory activities toward pp60^c‐Src tyrosine kinase were evaluated by in‐vitro kinase assay. Pre‐screening at two doses of compounds against kinase target revealed that, except for the N‐benzyl‐5‐phenyl indole imine derivatives 7a – 7d , all indole derivatives show the target inhibition at varying levels. Consequently, the compounds, 8c , 8f , 8g , and 8h , were selected for prescreening tests. The dose‐response curves for up to six concentrations (250 to 7.8 μM) of the active compounds were obtained by tyrosine kinase assay and the four‐parameter logistic analysis of these data resulted in the IC₅₀s of 4.69, 74.79, 75.06, and 84.23 μM for compounds 8c , 8f , 8g , and 8h , respectively. Therefore, compound 8c , 1‐(1‐benzyl‐5‐phenyl‐1H‐indole‐3‐yl)‐N‐(4‐fluorobenzyl)methanamine·HCl, was the promising inhibitor for pp60^c‐Src, followed by compounds 8g and 8h . Under the same conditions, compound 8f did not provide any reasonable inhibition pattern to be considered as active compound. Therefore, among all four active compounds, compound 8f was not found suitable for further analysis.     

Synthesis and in‐vitro Cytotoxicity of Poly‐functionalized 4‐(2‐Arylthiazol‐4‐yl)‐4H‐chromenes

A new series of 4‐aryl‐4H‐chromenes bearing a 2‐arylthiazol‐4‐yl moiety at the 4‐position were prepared as potential cytotoxic agents. The in‐vitro cytotoxic activity of the synthesized 4‐aryl‐4H‐chromenes was investigated in comparison with etoposide, a well‐known anticancer drug, using MTT colorimetric assay. Among them, the 2‐(2‐chlorophenyl)thiazol‐4‐yl analog 4b showed the most potent activity against nasopharyngeal epidermoid carcinoma KB, medulloblastoma DAOY, and astrocytoma 1321N1, and compound 4d bearing a 2‐(4‐chlorophenyl)thiazol‐4‐yl moiety at the 4‐position of the chromene ring exhibited the best inhibitory activity against breast cancer cells MCF‐7, lung cancer cells A549, and colon adenocarcinoma cells SW480 with IC₅₀ values less than 5 μM. The ability of compound 4b to induce apoptosis was confirmed in a nuclear morphological assay by DAPI staining in the KB and MCF‐7 cells.     

Discovery of Novel 2‐(piperidin‐4‐yl)‐1H‐benzo[d]imidazole Derivatives as Potential Anti‐Inflammatory Agents

A novel 2‐(piperidin‐4‐yl)‐1H‐benzo[d]imidazole derivative 5 with good anti‐inflammatory activity was identified from our in‐house library. Based on hit compound 5 , two series of 2‐(piperidin‐4‐yl)‐1H‐benzo[d]imidazole derivative 6a – g and 7a – h were designed and synthesized as novel anti‐inflammatory agents. Most of synthesized compounds exhibited good inhibitory activity on NO and TNF‐α production in LPS‐stimulated RAW 264.7 macrophages, in which the compound 6e showed most potent inhibitory activity on NO (IC₅₀ = 0.86 μm ) and TNF‐α (IC₅₀ = 1.87 μm ) production. Further evaluation revealed that compound 6e displayed more potent in vivo anti‐inflammatory activity than ibuprofen did on xylene‐induced ear oedema in mice. Additionally, Western blot analysis revealed that compound 6e could restore phosphorylation level of IκBα and protein expression of p65 NF‐κB in LPS‐stimulated RAW 264.7 macrophages.     

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.