Synthesis, Molecular Docking, and Biological Evaluation of Benzimidazole Derivatives as Selective Butyrylcholinesterase Inhibitors.

BACKGROUND: Benzimidazole is an interesting pharmacophore which has been extensively studied in medicinal chemistry due to its high affinity towards various enzymes and receptors. Its derivatives have been previously shown to possess a wide range of biological activities including anthelmintic, antihypertensive, antiulcer, as well as anticholinesterase activity. OBJECTIVE: The objective of this study is to search for more potent benzimidazole-based cholinesterase inhibitors, through the modification of the 1- and 2-positions of the benzimidazole core. METHODS: Synthesis of compounds were carried out via a 4-step reaction scheme following a previously reported protocol. Structure-activity relationship of the compounds are established through in vitro cholinesterase assays and in silico docking studies. Furthermore, cytotoxicity and blood brain barrier (BBB) permeability of the compounds were also investigated. RESULTS: Among the synthesised compounds, three of them (5IIa, 5IIb, and 5IIc) exhibited potent selective butyrylcholinesterase inhibition at low micromolar level. The compounds did not show any significant cytotoxicity when tested against a panel of human cell lines. Moreover, the most active compound, 5IIc, was highly permeable across the blood brain barrier. CONCLUSION: In total 10 benzimidazole derivatives were synthesized and screened for their AChE and BuChE inhibitory activities. Lead compound 5Iic, represents a valuable compound for further development as potential AD therapeutics.

Effect of nonmyeloablative unrelated fetal and neonatal murine peripheral blood mononuclear cell infusion on MRL/lpr mice.

For patients with refractory systemic lupus erythematosus (SLE), current medications are insufficient to control their condition, and new treatments are necessary. We investigated the effect of fetal and neonatal murine peripheral blood (FNPB) mononuclear cells on MRL/lpr lupus-prone mice. Female MRL/lpr mice were randomized to three groups (control, radiation and infusion groups). The infusion group had significantly better results for survival rate, body weight increase, reduction of spleen index, serum anti-ds-DNA antibody, antinuclear antibodies (ANA) and creatinine (Cr), 24 h urine protein and pathological renal tissue lesions than either the control or radiation group. Graft versus host disease (GVHD) was not observed in MRL/lpr mice in the infusion group. The infusion group also had better hematogenesis reconstruction than the radiation group. Flow cytometry analysis revealed a significant increase in Th1, CD8+ T and T reg cells and a reduction in Th2, CD4+ T and Th17 cells in the peripheral blood of the radiation and infusion groups compared with the control group. Immunocytochemical assay revealed a significant increase in serum transforming growth factor (TGF)-ß and a significant reduction in interleukin (IL)-17 in the radiation and infusion groups compared with the control group. Therefore, our study showed that FNPB mononuclear cell infusion has a significant role in regulating CD4+ T cells, Th1/Th2, Th17/T reg balance and their corresponding cytokines in MRL/lpr mice. The FNPB mononuclear cell infusion provided evidence in animals and suggested a potential clinical application for umbilical cord blood transplantation to treat SLE patients.

Nodal benign and malignant monocytoid B cells with and without follicular lymphomas: a comparative study of follicular colonization, light chain restriction, bcl-2, and t(14;18) in 39 cases.

As part of an effort to develop a better understanding of the relationship between nodal monocytoid B-cell lymphomas (MBCLs) and follicular lymphomas (FLs) when they coexist (MBCL + FL) and to assess the validity of the morphological criteria for the latter diagnosis, we evaluated follicular colonization, bcl-2 reactivity, light chain restriction, and the presence of t(14;18) in 14 benign lymph node specimens containing benign monoclonal B cells (MBCs), in eight nodal specimens of pure MBCL, and in 17 nodal specimens of MBCL coexisting with FL (MBCL + FL). Follicular colonization by malignant MBCs was observed in six specimens of pure MBCL and in 13 specimens of MBCL + FL. Benign MBCs did not express bcl-2 by immunohistological methods in 11 of 12 benign specimens. In contrast, weak reactivity for bcl-2 was detected in malignant MBCs in four of five specimens of pure MBCL and in the MBCL component in 13 of 15 specimens from the MBCL + FL group. In the FL component of 13 specimens, the bcl-2 was strongly positive. Identical light chain restriction was detected by immunohistological methods in both the FL component and the MBCL component in 15 specimens of MBCL + FL. Polymerase chain reaction analysis did not detect the t(14;18) translocation in any of 10 benign specimens or any of six evaluable pure MBCL specimens. In contrast, the translocation was detected in whole sections from eight of 12 specimens of MBCL + FL. Thus, on the one hand, the high incidences of follicular colonization and the coexistence of MBCL and FL as well as the identical light chain restriction in MBCL and FL components of MBCL + FL cases suggest that possibly these are related closely when they coexist. On the other hand, the bcl-2 and t(14;18) data cannot be used as evidence in support of a close relationship.