Novel Dibenzoazepine-Substituted Triazole Hybrids as Cholinesterase and Carbonic Anhydrase Inhibitors and Anticancer Agents: Synthesis, Characterization, Biological Evaluation, and In Silico Studies

Abstract

The new dibenzoazepine-substituted triazole hybrids (12−20) were designed by molecular hybridization approach and synthesized utilizing the Cu(I)-catalyzed click reaction. The hybrid structures (12−20) were obtained in high yields (74−98%) with a simple two-step synthesis strategy and fully characterized. These compounds were assessed for their influence on various metabolic enzymes including human carbonic anhydrase isoenzymes (hCA I and hCA II), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). The K i values for the compounds concerning hCA I, hCA II, AChE, and BChE enzymes were in the ranges 29. 94−121.69, 17.72−89.42, 14.09−44.68, and 1.15−48.82 nM, respectively. Compound 13 was 49.70-fold more active than tacrine (standard drug) for BChE and 5.49-fold for AChE. Compound 14 was 4.16-fold more active than acetazolamide (standard drug) for hCA I and 5.79-fold for hCA II. The cytotoxic effects of the synthesized click products were investigated on human triple-negative breast cancer cell lines. The IC 50 values of the most effective compounds were calculated between 12.51 ± 1.92 and 18.07 ± 2.14 μM in MDA-MB-231 and BT-549 cells. Molecular docking and ADME predictions were performed. Then, in vitro effective compounds were analyzed by molecular dynamics (MD) simulation and MM/GBSA calculation. Consequently, click products showed good cytotoxicity and inhibition potential on colony formation in cancer cells.

Repurposing of FDA‐Approved Drugs as Acetylcholinesterase Inhibitors for Alzheimer's Disease: A Combined In Silico and In Vitro Evaluation and Structure–Activity Relationship

“…In our previous study, we reported that pantoprazole would be a potential FOXM1 inhibitor for the treatment of breast cancer [ 77 ]. In the previous studies, the IC 50 values for AChE inhibition were reported for TCR and DNP as 77.41 ± 3.12 nM and 0.021 ± 0.001 µM, respectively [ 41,78 ]. The values in our study are consistent with the literature for the standard comparison of TCR and DNP.…”

“…In our previous studies, the binding residues, such as Tyr337, Tyr341, Trp286, Phe295, Phe338, Asp74, and Trp86, have been reported [ 38, 41, 46, 47 , 58 ]. We showed in a study that reference drug TCR interacted with Trp82 through pi-pi interaction [ 41 ]. The interactions and key residues of DNP targeting AChE were shown in several reported studies [ 32,[59][60][61].…”

Repurposing of FDA‐Approved Drugs as Acetylcholinesterase Inhibitors for Alzheimer's Disease: A Combined In Silico and In Vitro Evaluation and Structure–Activity Relationship

“…In our previous study, we reported that pantoprazole would be a potential FOXM1 inhibitor for the treatment of breast cancer [ 77 ]. In the previous studies, the IC 50 values for AChE inhibition were reported for TCR and DNP as 77.41 ± 3.12 nM and 0.021 ± 0.001 µM, respectively [ 41,78 ]. The values in our study are consistent with the literature for the standard comparison of TCR and DNP.…”

“…In our previous studies, the binding residues, such as Tyr337, Tyr341, Trp286, Phe295, Phe338, Asp74, and Trp86, have been reported [ 38, 41, 46, 47 , 58 ]. We showed in a study that reference drug TCR interacted with Trp82 through pi-pi interaction [ 41 ]. The interactions and key residues of DNP targeting AChE were shown in several reported studies [ 32,[59][60][61].…”

Design, Synthesis, In Vitro Biological Evaluation, and In Silico Analyses of Novel Pyrano[3,4- b ]indole-Containing Compounds as Promising Multitarget Candidates for Alzheimer’s Disease and Cancer Therapy

“…In our previously reported studies, the IC 50 values of tacrine for AChE were found to be 77.41 ± 3.12 nM, 74.23 ± 0.83 nM and 68.46 ± 0.42 nM, and for BChE 45.43 ± 4.46 nM. , − Rivastigmine is a dual inhibitor of AChE and BChE and is known to have IC 50 values at micromolar (μM) concentrations. Consequently, the newly synthesized pyrano­[3,4- b ]­indole-based compounds were determined to be potential inhibitors of AChE and BChE at nanomolar concentrations.…”

“…In recent years, many researchers have reported the discovery and development of new and effective AChE inhibitors for the treatment of AD. , − , − H-bonding, pi–pi stacking, and pi–pi cation interactions have been observed in the binding pocket of AChE with critical residues such as Phe295, Tyr341, Phe338, Arg296, Gly121, Tyr337, His447, Trp86, and Trp286 between the target enzyme and natural-synthetic hybrid compounds. The active site of AChE has been reported to contain subregions with various amino acid residues such as Phe295, Trp86, Trp286, and Tyr337.…”

Novel Sulfonylhydrazones With Sulfonate Ester Framework: Promising Dual Inhibitors of AChE and hCAs

“…AD is a progressive brain disorder that gradually impairs memory and cognitive abilities, eventually rendering individuals unable to perform even the simplest tasks [ 66 , 67 ]. Behavioral and personality changes are also common in AD patients.…”

Repurposing of FDA‐Approved Drugs as Acetylcholinesterase Inhibitors for Alzheimer's Disease: A Combined In Silico and In Vitro Evaluation and Structure–Activity Relationship

“…In our previous study, we reported that pantoprazole would be a potential FOXM1 inhibitor for the treatment of breast cancer [ 77 ]. In the previous studies, the IC 50 values for AChE inhibition were reported for TCR and DNP as 77.41 ± 3.12 nM and 0.021 ± 0.001 µM, respectively [ 41,78 ]. The values in our study are consistent with the literature for the standard comparison of TCR and DNP.…”

“…In our previous studies, the binding residues, such as Tyr337, Tyr341, Trp286, Phe295, Phe338, Asp74, and Trp86, have been reported [ 38, 41, 46, 47 , 58 ]. We showed in a study that reference drug TCR interacted with Trp82 through pi-pi interaction [ 41 ]. The interactions and key residues of DNP targeting AChE were shown in several reported studies [ 32,[59][60][61].…”

Design, Synthesis, In Vitro Biological Evaluation, and In Silico Analyses of Novel Pyrano[3,4- b ]indole-Containing Compounds as Promising Multitarget Candidates for Alzheimer’s Disease and Cancer Therapy

“…In our previously reported studies, the IC 50 values of tacrine for AChE were found to be 77.41 ± 3.12 nM, 74.23 ± 0.83 nM and 68.46 ± 0.42 nM, and for BChE 45.43 ± 4.46 nM. , − Rivastigmine is a dual inhibitor of AChE and BChE and is known to have IC 50 values at micromolar (μM) concentrations. Consequently, the newly synthesized pyrano­[3,4- b ]­indole-based compounds were determined to be potential inhibitors of AChE and BChE at nanomolar concentrations.…”

“…In recent years, many researchers have reported the discovery and development of new and effective AChE inhibitors for the treatment of AD. , − , − H-bonding, pi–pi stacking, and pi–pi cation interactions have been observed in the binding pocket of AChE with critical residues such as Phe295, Tyr341, Phe338, Arg296, Gly121, Tyr337, His447, Trp86, and Trp286 between the target enzyme and natural-synthetic hybrid compounds. The active site of AChE has been reported to contain subregions with various amino acid residues such as Phe295, Trp86, Trp286, and Tyr337.…”

Novel Sulfonylhydrazones With Sulfonate Ester Framework: Promising Dual Inhibitors of AChE and hCAs

“…AD is a progressive brain disorder that gradually impairs memory and cognitive abilities, eventually rendering individuals unable to perform even the simplest tasks [ 66 , 67 ]. Behavioral and personality changes are also common in AD patients.…”

Repurposing of FDA‐Approved Drugs as Acetylcholinesterase Inhibitors for Alzheimer's Disease: A Combined In Silico and In Vitro Evaluation and Structure–Activity Relationship

“…In our previous study, we reported that pantoprazole would be a potential FOXM1 inhibitor for the treatment of breast cancer [ 77 ]. In the previous studies, the IC 50 values for AChE inhibition were reported for TCR and DNP as 77.41 ± 3.12 nM and 0.021 ± 0.001 µM, respectively [ 41,78 ]. The values in our study are consistent with the literature for the standard comparison of TCR and DNP.…”

“…In our previous studies, the binding residues, such as Tyr337, Tyr341, Trp286, Phe295, Phe338, Asp74, and Trp86, have been reported [ 38, 41, 46, 47 , 58 ]. We showed in a study that reference drug TCR interacted with Trp82 through pi-pi interaction [ 41 ]. The interactions and key residues of DNP targeting AChE were shown in several reported studies [ 32,[59][60][61].…”

Design, Synthesis, In Vitro Biological Evaluation, and In Silico Analyses of Novel Pyrano[3,4- b ]indole-Containing Compounds as Promising Multitarget Candidates for Alzheimer’s Disease and Cancer Therapy

“…In our previously reported studies, the IC 50 values of tacrine for AChE were found to be 77.41 ± 3.12 nM, 74.23 ± 0.83 nM and 68.46 ± 0.42 nM, and for BChE 45.43 ± 4.46 nM. , − Rivastigmine is a dual inhibitor of AChE and BChE and is known to have IC 50 values at micromolar (μM) concentrations. Consequently, the newly synthesized pyrano­[3,4- b ]­indole-based compounds were determined to be potential inhibitors of AChE and BChE at nanomolar concentrations.…”

“…In recent years, many researchers have reported the discovery and development of new and effective AChE inhibitors for the treatment of AD. , − , − H-bonding, pi–pi stacking, and pi–pi cation interactions have been observed in the binding pocket of AChE with critical residues such as Phe295, Tyr341, Phe338, Arg296, Gly121, Tyr337, His447, Trp86, and Trp286 between the target enzyme and natural-synthetic hybrid compounds. The active site of AChE has been reported to contain subregions with various amino acid residues such as Phe295, Trp86, Trp286, and Tyr337.…”

Novel Sulfonylhydrazones With Sulfonate Ester Framework: Promising Dual Inhibitors of AChE and hCAs

“…AD is a progressive brain disorder that gradually impairs memory and cognitive abilities, eventually rendering individuals unable to perform even the simplest tasks [ 66 , 67 ]. Behavioral and personality changes are also common in AD patients.…”