SAR Evaluation of Disubstituted Tacrine Analogues as Promising Cholinesterase and Carbonic Anhydrase Inhibitors

Background: The inhibition of both hydrolysis products of acetylcholine (ACh), Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE), is essential for successful treatment of Alzhemier patients. Objectives: This study was investigated inhibition potentials of recently synthesized disubstituted tacrines derivatives on going our research against AChE, BChE and carbonic anhydrase cyctosolic (hCA I and H) enzymes to explore the Structure activity relationship (SAR). Methods: Inhibitory activities of tested compounds against AChE and BChE were measured by spectrophotometric method, developed by Ellman et al. Furthermore, the disubstituted tacrines were determined as inhibitors of two physiologically relevant CA isoforms, the cytosolic hCA I and H by an esterase assay method. Results: The silyl, thiomethyl and cyano substituted seven membered hydrocycle tacrines (9, 11 and 14) significantly inhibited AChE, compared with starting compound 3 (6,8-dibromo-2,3,4,5-teytrahydro-1H-cyclohepta[1,2-b] quinoline) and reference compounds, galantamine and tacrine, while methoxy substituted seven membered hydrocycle tacrine derivative 10 showed selective inhibition against BChE (IC50 = 563 nM). Interestingly, disubstituted tacrines displayed higher or parallel inhibition to galantamine. Additionally, all these tacrine analogues were recorded to be powerful inhibitor compounds of the cytosolic isoenzyme hCA I with K-i in the range of 43.81-471.67 nM, as well as a moderate selectivity toward hCA II isoenzyme with K-i in the range from 87.14 to 614.68 nM compared with AZA, as standard. Conclusion: The disubstituted seven membered hydrocycle tacrine analogues 9-12 and 14 may have promising anti Alzhemier drug candidate and dibromo six membered hydrocycle 2 and dibromo seven membered hydrocycle 3 derivatives may be novel hCA I and II enzyme inhibitors

Synthesis, characterization, and SAR of arylated indenoquinoline-based cholinesterase and carbonic anhydrase inhibitors

We report the synthesis of bromoindenoquinolines (15a-f) by Friedlander reactions in low yields (13-50%) and the conversion of the corresponding phenyl-substituted indenoquinoline derivatives 16-21 in high yields (80-96%) by Suzuki coupling reactions. To explore the structure-activity relationship (SAR), their inhibition potentials to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase cyctosolic (hCA I and II) enzymes were determined. Monophenyl (16-18) indenoquinolines significantly inhibited the AChE and BChE enzymes in ranges of IC50 37-57nM and 84-93nM, respectively, compared with their starting materials 15a-c and reference compounds (galanthamine and tacrine). On the other hand, these novel arylated indenoquinoline-based derivatives were effective inhibitors of the BChE, hCA I and II, BChE and AChE enzymes with K-i values in the range of 37 +/- 2.04 to 88640 +/- 1990nM for AChE, 120.94 +/- 37.06 to 1150.95 +/- 304.48nM for hCA I, 267.58 +/- 98.05 to 1568.16 +/- 438.67nM for hCA II, and 84 +/- 3.86 to 144120 +/- 2910nM for BChE. As a result, monophenyl indenoquinolines 16-18 may have promising anti-Alzheimer drug potential and 3,8-dibromoindenoquinoline amine (15f) can be novel hCA I and hCA II enzyme inhibitors

Combined surgical and chemotherapy treatment for invasive primary urethral cancer: a case presentation

Abstract Background The European Association of Urology (EAU) defines primary urethral carcinoma (PUC) as a carcinoma that arises in the urethra without a previous diagnosis of carcinoma elsewhere in the urinary system. It is considered as a rare cancer, accounting for less than 1% of all malignant tumors and 5% of malignant tumors of the urinary system. The difficulty in diagnosis and its rarity can lead to delayed diagnosis and decreased survival. We think that a case report to be made in the literature for this rare disease with no consensus on treatment will contribute to disease management. Case presentation In this article, we describe the diagnosis and treatment process of a 75-year-old patient who was diagnosed with primary urethral cancer and had urethral discharge and difficulty in urination. The biopsy result from the suspected hyperemic area in the urethra in cystourethroscopy was primary urethral cancer. Urethrectomy followed by urethroplasty was performed on the patient's 2-cm primary urethral cancerous tissue. In the postoperative first month, an F-18 FDG whole-body PET scan for oncological evaluation showed increased pathological F-18 FDG uptake in the periphery of the mass in the penile urethra and indistinguishable boundaries from the prostatic urethra. After this, adjuvant gemcitabine and carboplatin therapy was planned by the oncology team. Conclusions Based on our outcome in this case, we believe that chemotherapy combined with surgery increases the chance of successful treatment in locally advanced urethral cancer