Development of novel 9H-carbazole-4H-chromene hybrids as dual cholinesterase inhibitors for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease affecting mental ability and neurocognitive functions. Cholinesterase enzymes affect concentration of acetylcholine in the brain, leading to dementia. Thus, there is an urgent need to develop novel dual cholinesterase inhibitors as possible anti-AD drugs. Herein, we have designed and synthesized a novel series of 9H-carbazole-4H-chromenes 4(a-l) through a one-pot three-component reaction of salicylaldehydes (1), hydroxycarbazole (2) and N-methyl-1-(methylthio)-2-nitroethenamine (3) using triethylamine as a catalyst in ethanol. Synthetic transformation involves the formation of two C-C bonds and one C-O bond in a single step to obtain desired analogs. The rapid one-pot reaction does not require chromatographic purification, proceeds under mild conditions, and exhibits good tolerance toward various functional groups with high synthetic yields. Synthesized compounds were screened for cytotoxicity using MTT assay in BV-2 microglial cells. These compounds were then in-vitro screened against acetylcholinesterase (AChE) and butyrylcholinestrase (BuChE) enzymes. Most of these ligands have shown dual cholinesterase inhibitory activity compared to the standard drug. In-vitro results showed that the compounds 4a and 4d have promising anticholinesterase response against both cholinesterase enzymes (4a, AChE IC50: 5.76 µM, BuChE IC50: 48.98 µM; 4d, AChE IC50: 3.58 µM, BuChE IC50: 42.73 µM). In-vitro results were validated by molecular docking and dynamic simulation at 100 ns. Molecular docking and molecular dynamics simulation study strongly supported structural features present in these analogs. Together, these analogs could be exploited to develop dual anti-cholinesterase candidates to treat AD in combination with other drugs.

Isocyanide-based Multicomponent Reactions (IMCRs) in Water or Aqueous Biphasic Systems.

BACKGROUND: Isocyanide is an intriguing one-carbon synthon that is frequently employed in a variety of carbon-carbon and carbon-heteroatom bond-forming reactions. Isocyanide-based multicomponent reactions (IMCRs) are effective synthetic tools in organic synthesis for the preparation of complex heterocyclic molecules. The IMCRs in water have become an attractive research direction, enabling simultaneous growth of both IMCRs and green solvents towards ideal organic synthesis. OBJECTIVE: The goal of this review is to provide a general overview of IMCRs in water or biphasic aqueous systems for accessing various organic molecules, as well as an examination of their benefits and mechanistic insights. CONCLUSION: High atom economies, mild reaction conditions, high yields, and catalyst-free processes are crucial features of these IMCRs in water or biphasic aqueous systems.

Design, synthesis, and pharmacological evaluation of [1, 3] dioxolo-chromeno[2,3-b]pyridines as anti-seizure agents.

An efficient one-pot three-component reaction for the synthesis of [1,3]dioxolo[4',5':6,7]chromeno[2,3-b]pyridines 4(a-i) has been developed. Synthesis was achieved by reacting sesamol (1), aromatic aldehydes 2(a-i), and 2-aminopropene-1,1,3-tricarbonitrile (3) in the presence of triethylamine at 100 °C under neat reaction condition. Simple operational procedure, broad substrate scope, column chromatography free separations, and high yield of products make it an efficient and largely acceptable synthetic strategy. Synthesized compounds 4(a-i) were further screened for preliminary anticonvulsant activity using MES and scPTZ tests. These analogs were also checked for neurotoxicity and hepatotoxicity. Selected active compounds have been then screened quantitatively to determine ED50 and TD50 values. Analog 4h was found effective in both preclinical seizure models with significant therapeutic/toxicity profile (4h: ED50 = 34.7 mg/kg, MES test; ED50 = 37.9 mg/kg, scPTZ test; TD50 = 308.7 mg/kg). Molecular dynamic simulation for 100 ns of compound 4h-complexed with GABAA receptor revealed good thermodynamic behavior and fairly stable interactions (4h, Docking score = - 10.94). In conclusion, effective synthetic strategy, significant anticonvulsant activity with good toxicity profile and detailed molecular modeling studies led us to anticipate the emergence of these analogs as valid leads for the development of future effective neurotherapeutic agents.

Arylidenemalononitriles as Versatile Synthons in Heterocyclic Synthesis.

BACKGROUND: Arylidenemalononitriles are valuable synthons for the construction of a variety of novel complex heterocyclic motifs, fused heterocycle derivatives, and spirocyclic compounds. They are versatile chemical intermediates and have increasing applications in industry, agriculture, medicine, and biological science. OBJECTIVE: The aim of this review is to highlight the preparation methods and reactions of arylidenemalononitriles in the synthesis of various heterocyclic compounds. CONCLUSION: In this review, we have presented the application of arylidenemalononitriles to construct a variety of heterocycles. Various catalysts for the preparation of arylidnemalononitriles have been described.

A Review on Thiocyanation of Indoles.

BACKGROUND: The thiocyanation of indoles is a direct way for carbon-sulfur bond formation to access 3-thiocyanato-indoles. 3-thiocyanato-indoles exhibit potent biological and pharmacological activities and also serve as building blocks to synthesize many biologically active sulfur-containing indole derivatives. OBJECTIVE: The aim of this review is to highlight different approaches for the thiocyanation of indoles focusing on its scope and mechanism. CONCLUSION: In this review, we have summarized various methods for the thiocyanation of indoles. Selection of new methods for the preparation of 3-thiocyanato-indoles will be done. The mechanistic aspects and significance of the methods are also briefly discussed.

Rationale Design, Synthesis, Cytotoxicity Evaluation, and Molecular Docking Studies of 1,3,4-oxadiazole Analogues.

BACKGROUND: 1,3,4-Oxadiazole heterocycles possess a broad spectrum of biological activities. They were reported as potent cytotoxic agents and tubulin inhibitors; hence it is of great interest to explore new oxadiazoles as cytotoxic agents targeting tubulin polymerization. OBJECTIVE: Two new series of oxadiazoles (5a-h and 12a-h) were synthesized, structurally related to the heterocyclic linked aryl core of IMC-038525, NSC 776715, and NSC 776716, with further modification by incorporating methylene linker. METHOD: The 2,5-disubstituted-1,3,4-oxadiazoles (5a-h and 12a-h) were synthesized by refluxing an equimolar mixture of the intermediates [(4) and (8a-d)] and aromatic aldehydes in water-ethanol system using sodium bisulphite catalyst. The cytotoxicity evaluation was carried out according to the National Cancer Institute (NCI US) Protocol, while the tubulin polymerization assay kits from Cytoskeleton ™(bk011p) was used to perform an in vitro tubulin polymerization assay. RESULTS: 2-(5-{[(4-Chlorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)phenol (5f) and 2-[(2,4-dichlorophenoxy) methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole (12c) showed maximum cytotoxicity with the mean percent growth inhibitions (GIs) of 71.56 and 72.68 respectively at 10 µM drug concentrations. Both the compounds (5f and 12c) showed superior cytotoxicity than clinically prevalent anticancer drugs, Imatinib and Gefitinib in one dose assay. The compound 12c showed promising results in five dose assay, with GI50 values varies between 1.61 and >100 µM. Furthermore, the compounds, 5f and 12c also inhibited the polymerization of tubulin with, an IC50 of 2.8 and 2.2 µM, respectively. CONCLUSION: The oxadiazoles reported herein are tubulin inhibitors and cytotoxic agents. These findings will be helpful in future drug design of more potent tubulin inhibitor cytotoxic agents.

Synthesis and biological evaluation of novel pyrano[3,2-c]carbazole derivatives as anti-tumor agents inducing apoptosis via tubulin polymerization inhibition.

A series of novel pyrano[3,2-c]carbazole derivatives have been synthesized by a simple one-pot, three component reaction of aromatic aldehydes, malononitrile-ethyl cyanoacetate and 4-hydroxycarbazoles catalyzed by triethylamine. The antiproliferative activity of the derivatives on various cancer cell lines such as MDA-MB-231, K562, A549 and HeLa was investigated. Among 9a-p, congeners 9a, 9c, 9g and 9i showed profound antiproliferative activity with IC50 values ranging from 0.43 to 8.05 µM and induced apoptosis significantly by inhibiting tubulin polymerization. Cell-based biological assays demonstrated that treatment of cell lines with compounds 9a, 9c, 9g and 9i results in G2/M phase arrest of the cell cycle. Moreover the derivatives significantly disrupted the microtubule network, produced an elevation of cyclinB1 protein levels and induced apoptosis by increasing the caspase-3 levels. In particular, 9i strongly inhibited tubulin assembly compared to the positive control CA-4. Molecular docking studies demonstrated that all the lead compounds selectively occupy the colchicine binding site of the tubulin polymer.