Dual-target ligand discovery for Alzheimer's disease: triphenylphosphoranylidene derivatives as inhibitors of acetylcholinesterase and ß-amyloid aggregation.

Alzheimer disease (AD) is one of the major neurodegenerative diseases that could not be prevented or completely cured and may lead to death. Here, we target AChE and ß-amyloid proteins. Synthesising new triphenylphosphporanylidene derivatives based on the surveyed literature and testing their biological activity revealed promising results especially for the acetyl triphenylphosphoranylidene derivative 8c, which showed good inhibitor activity against AChE enzyme with IC50 in the nanomolar range (97.04 nM); on the other hand, it showed poor selectivity for AChE versus butyrylcholinesterase but with some futural structural modification, this selectivity can be improved. 8c showed MMP-2 IC50 of 724.19 nM and Aß1-42 aggregation IC50 of 302.36 nM. A kinetic study demonstrated that compound 8c uncompetitively inhibited AChE. Moreover, derivative 8c showed low cytotoxicity, good in vivo behavioural studies including Y-maze and passive avoidance tests with activity similar to that of donepezil. Finally, in silico studies for 8c predict its good penetration into BBB and good binding affinity in the AChE binding site.

The synthesis and antineoplastic activities of thiaziridine, sulfidometylphosphonium, and dithiaphosphitane-sulfide against the Ehrlich ascites carcinoma.

Phosphonium compounds offer an attractive branch of research that chemists and biologists apply for producing many novel drugs for various applications, and its polymeric ingredients are composed of quaternary ammonium and phosphonium salts. The reactions of isothiocyanate with phosphinimine bestow thiaziridine, carbamate, and thiourea derivatives. Moreover, isothiocyanate reacts with tris (dimethylamino) phosphine leading to the formation of sulfidomethyl phosphonium. Lawesson's and Japanese reagents have potential to react with isothiocyanates to generate dithiaphosphetane sulfides. Treatment of isocyanate with Lawesson' s or Japanese reagents under reflux conditions affords thiaphosphetidinone sulfide, but when applied at room temperature, the dithiaphosphetane sulfide was isolated. Ehrlich ascites carcinoma (EAC) mice model was used to investigate potential anticancer properties of the novel phosphonium and thiophosphate derivatives. Synthesized compounds (100 mg/kg b.w.) were administered orally to the EAC-bearing mice for about 2 weeks. Compounds' antineoplastic activity was determined by the evaluation of volume, viability, and inhibition percent of EAC cells. In addition, DNA fragmentation percent was assessed. The expression of apoptotic marker genes (Bax, Bcl2, Caspase 3) and encoding proinflammatory cytokines (TNF-α) and pro-apoptotic protein (p53) were inspected by real time-quantitative polymerase chain reaction (RT-qPCR). The overall conclusion was based on the findings that treatment with synthesized compounds leads to decrease in tumor volume, increase in tissue DNA fragmentation, downregulation of Bcl2 gene, and upregulation of Bax, caspase3, and p53 markers, along with decrease in TNF-α level in liver tissues. These findings suggest that the anticancer mechanism of these compounds is based on the programmed cell death (Apoptosis).

Design, synthesis, biological evaluation, and molecular docking of new benzofuran and indole derivatives as tubulin polymerization inhibitors.

Microtubules and the mitotic spindle have become an important target for cancer treatment due to their critical role in cell division. In this work, a novel series of benzofuran and indole derivatives were designed and synthesized, to be evaluated as tubulin polymerization inhibitors. 2-Acetylbenzofuran derivatives 1a,b and 3-acetylindole 1c were condensed with Wittig reagents 2a-d and Wittig-Horner reagents 3a-e to afford the respective 2-ethylidene derivatives 5a-j and 7a-e. Also, iminomethylene triphenylphosphine (2e) reacted with 1a,b to afford benzofuran-2-ylethylidene aniline derivatives 6a,b. In addition, compounds 1a,b reacted with trialkylphosphites 4a-c to give 1:1 adduct for which the Oxaphospholo[4,3-b]benzofuran-7-yl)diazene derivatives 8a-f, were assigned. The possible reactions mechanisms were discussed and structural reasoning for the new compounds were based upon spectroscopic data. Their antiproliferative activities against two cell lines namely, HepG2 and MCF7 cells were then evaluated. It was found that the benzofuran compounds 5b, 6a, and 8c exhibited the strongest antiproliferative activities against both cell lines compared to doxorubicin. By studying the mechanism of action, compound 6a showed good inhibition of tubulin polymerization which leads to mitotic spindle formation disruption, cell cycle arrest in the G2/M phase, and apoptosis of HepG2 cells. A conducted docking study confirmed the in vitro results indicating that compound 6a fitted properly at the colchicine binding site of tubulin. Based on these findings, compound 6a can be considered as a promising anticancer candidate that can be subjected for further development as a tubulin polymerization inhibitor for treating liver and breast cell carcinoma.

Synthesis, biological evaluation and molecular docking of new sulfonamide-based indolinone derivatives as multitargeted kinase inhibitors against leukemia.

Series of novel sulfonamide-based 3-indolinones 3a-m and 4a-f were designed, synthesized and then their cytotoxic activity was evaluated against a panel of sixty cancer cell lines. This screening indicated that 4-(2-(5-fluoro-2-oxoindolin-3-ylidene)acetyl)phenyl benzenesulfonate (4f) possessed promising cytotoxicity against CCRF-CEM and SR leukemia cell lines with IC50 values 6.84 and 2.97 µM, respectively. Further investigation of the leukemic cytotoxicity of compound 4f was carried out by performing PDGFRα, VEGFR2, Aurora A/B and FLT3 enzyme assays and CCRF-CEM and SR cell cycle analysis. These investigations showed that compound 4f exhibited pronounced dual inhibition of both kinases PDGFRα and Aurora A with potency of 24.15 and 11.83 nM, respectively. The in vitro results were supported by molecular docking studies in order to explore its binding affinity and its key amino acids interactions. This work represents compound 4f as a promising anticancer agent against leukemia.

Synthesis, molecular docking and biological evaluation of 2-(thiophen-2-yl)-1H-indoles as potent HIV-1 non-nucleoside reverse transcriptase inhibitors.

New 2-(thiophen-2-yl)-1H-indole derivatives bearing hydrophobic substituents at the 3-position were designed, synthesized and evaluated for their inhibition of HIV-1 reverse transcriptase (RT) enzyme. Dialkylphosphites (2a-c) or trialkylphosphites (3a-c) were reacted with 2-(thiophen-2-yl)-1H-indole-3-carbaldehyde (1) yielding the corresponding α-hydroxyphosphonate adducts (7a-7c). The reaction of compound 1 with the ylidenetriphenylphosphoranes (4a-4c) proceeds via Wittig mechanism giving the corresponding ethylenes (E, 8a-c). Compounds 8b,c were equally obtained upon reacting aldehyde 1 with the appropriate dialkylphosphonates 5a,b under the Horner-Wittig reaction conditions. On the other hand, the reaction of aldehyde 1 with diethyl cyanomethylene phosphonate (5c) yielded a mixture of the E-ethylene 10 and the cyanovinyl phosphonate 11. The thioaldehyde 12 was obtained upon refluxing aldehyde 1 with the Lawesson's reagent (LR, 6a) or with the Japanese reagent (JR, 6b) in dry toluene. Upon evaluation of HIV-1 Reverse Transcriptase enzyme inhibition, compound 8b (IC50 = 2.93 nM) exhibited the superior HIV-1 RT inhibition and its potency was about 3-folds that of Efavirenz (IC50 = 6.03 nM). Also, compounds 9a (IC50 = 4.09 nM) and 12 (IC50 = 3.54 nM) showed significantly higher inhibition potency. Moreover, compounds 7b (IC50 = 7.48 nM), and 8a (IC50 = 4.55 nM) showed potency not significantly different from that of Efavirenz. Molecular docking experiments on these potent compounds was in accordance with the in vitro data and confirmed binding of these compounds to the enzyme through ring-stacking and hydrogen bond interactions. According to these results, the new molecules would serve as potent HIV-1 NNRTIs inhibitors.

New phosphazine and phosphazide derivatives as multifunctional ligands targeting acetylcholinesterase and ß-Amyloid aggregation for treatment of Alzheimer's disease.

Phosphazine and phosphazide derivatives are described herein as a new class of selective and potent acetylcholinesterase (AChE) inhibitors and ß-amyloid aggregation inhibitors. Phosphazines (5-7) were synthesized smoothly via a redox-condensation reaction of 1,2-bis(diphenylphosphino)ethane with different amines derivatives in the presence of dialkyl azodicarboxylate (Staudinger reaction) while phosphazides (8) via electrophilic attack of azido derivatives. Structures of the synthesized compounds were justified on the basis of compatible elementary and spectroscopic analyses. All the compounds were evaluated for their acetylcholinesterase inhibitory activity. The most three potent compounds (5b-c and 8b) showing AChE IC50 values (29.85-34.96 nM) comparable to that of donepezil (34.42 nM) were subjected to further investigation by testing their butyrylcholinesterase, MMP-2 and self-induced Aß aggregation inhibition activity. Especially, the coumarin phosphazide derivative (8b) presented the best AChE inhibition selectivity index (IC50 = 34.96 nM, AChE/BuChE; 3.81) together with good inhibition ability against MMP-2 (IC50 = 441.33 nM) and self-induced Aß1-42 aggregation (IC50 = 337.77 nM). In addition, the inhibition of metal-induced Aß aggregation by 8b was confirmed by thioflavine T fluorescence. The most potent effect of 8b was observed on the Zn2+-induced Aß42 aggregation. Kinetic study of compound 8b suggested it to be a competitive AChE inhibitor. Also, it specifically chelates metal and is predicted to be permeable to BBB. It also possesses low toxicity on SH-SY5Y neuroblastoma cells with a safety index of 15.37. In addition, it was demonstrated that compound 8b can improve the cognitive impairment of scopolamine-induced model in mice with % alternations and transfer latency time comparable to that of donepezil. Also, a docking study was carried out and it was in accordance with the in vitro results. These promising in vitro and in vivo findings highlight compound 8b as a possible drug candidate in searching for new multifunctional AD drugs.

Design, synthesis and biological evaluation of novel α-aminophosphonate oxadiazoles via optimized iron triflate catalyzed reaction as apoptotic inducers.

α-aminophosphonate oxadiazoles (5a-m) were prepared in high yields by reacting of 1,3,4-oxadiazole acetohydrazide (3) with appropriate aldehydes and diethyl phosphite under Kabachnik-Fields conditions using Iron triflate as a catalyst. The reaction conditions were optimized using D-optimal experimental design. Possible reaction mechanisms were considered, and structures of the new products were based upon compatible elementary and spectroscopic evidence. In vitro antitumor activities of these compounds were evaluated against human cancer cell lines of colon (HCT116), breast (MCF7) and liver (HepG2) and compared with anticancer drug, Doxorubicin, employing standard MTT assay. Compounds 5i and 5l demonstrated good antiproliferative activities against HCT116 tumor cells comparable to doxorubicin with low cytotoxicity towards normal fetal colon cell (FHC). Additionally, their capacity to activate apoptosis cascade was studied in HCT116 cell line by investigating the activation of proteolytic caspases cascade, the levels of Cytochrome C, Bax and Bcl-2. Active caspase-3 level was enhanced by 6-8-folds in HCT116 cell line when stimulated with compounds 5i and 5l compared to the control. The level of Caspases 8 & 9 was also increased signifying that intrinsic and extrinsic pathways are both activated. They also induced Bax and down regulated Bcl-2 protein level in addition to over-expressing Cytochrome C level in HCT116 cell line. Also, HCT116 cell cycle was mainly arrested at the Pre-G1 and G2/M phases when treated with compounds 5i and 5l.