Potential of Tryptamine Derivatives as Multi-Target Directed Ligands for Alzheimer's Disease: AChE, MAO-B, and COX-2 as Molecular Targets.

Extensive research has been dedicated to develop compounds that can target multiple aspects of Alzheimer's disease (AD) treatment due to a growing understanding of AD's complex multifaceted nature and various interconnected pathological pathways. In the present study, a series of biological assays were performed to evaluate the potential of the tryptamine analogues synthesized earlier in our lab as multi-target-directed ligands (MTDLs) for AD. To assess the inhibitory effects of the compounds, various in vitro assays were employed. Three compounds, SR42, SR25, and SR10, displayed significant AChE inhibitory activity, with IC50 values of 0.70 µM, 0.17 µM, and 1.00 µM, respectively. These values superseded the standard drug donepezil (1.96 µM). In the MAO-B inhibition assay, SR42 (IC50 = 43.21 µM) demonstrated superior inhibitory effects as compared to tryptamine and other derivatives. Moreover, SR22 (84.08%), SR24 (79.30%), and SR42 (75.16%) exhibited notable percent inhibition against the COX-2 enzyme at a tested concentration of 100 µM. To gain insights into their binding mode and to validate the biological results, molecular docking studies were conducted. Overall, the results suggest that SR42, a 4,5 nitro-benzoyl derivative of tryptamine, exhibited significant potential as a MTDL and warrants further investigation for the development of anti-Alzheimer agents.

Determination of ionization constant and drug-likeness prediction of synthetic isoniazid derivatives.

Determination of ionization constant, commonly termed pKa is of prime interest in a wide range of pharmaceutical Research fields. The pKa of a compound is critical as it influences on its physicochemical parameters in biological and environmental systems. The study of pKa is also essential not only for the formulation of drugs and optimization of a variety of novel analytical methods, establishing new pharmaceutical dosage forms yet the exploration of the mechanism of action of drugs. In this research work, we have determined pKa values of isoniazid (INH) derivatives; N'-[(4-methyl benzoyl)] pyridine-4-carbohydrazide (I) and [2-oxo-2-(4-phenyl phenyl) ethyl] (pyridine-4-yl formamido) azanium bromide (II) through UV- spectrophotometry, a method is known for the accuracy and precision of results. These two compounds (I and II) were synthetically prepared in our lab by derivatizing INH and reported by Naeem et al in the year 2014. The mean pKa values for compounds I and II were experimentally determined as 7.37 and 3.76 respectively. The study is helpful in understanding the physicochemical behavior of these compounds in a biological system. Different pharmacokinetic parameters were also predicted using online web tools which ensured significant drug-likeness for both compounds.

Synthesis, biological screening and docking studies of some indole derivatives as potential antioxidant.

The present study envisioned some antioxidant candidates having 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (TRY), 3-(2-bromoethyl)indole (BEI) and 7-azindole (AI) nucleus. Derivatives of these indole molecules were synthesized and their scavenging activity for reactive oxygen species (ROS) investigated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. T3, T42 exhibited significant radical scavenging potential which is comparable to ascorbic acid (standard), while T36 appeared as most potent antioxidant by displaying better scavenging activity than standard molecule. Molecular docking study revealed good binding score and interactions of T36 with target human antioxidant enzyme (PDB code: 3MNG) validating the results of biological activity.

Computation-based experimentation: Identification of piperazine containing antidepressants.

Depression, a common mental disorder, is one of the major contributors to the overall global burden with more than 264 million individuals affected worldwide. Monoamine oxidase inhibitors (MAOIs) have well-known efficacy for treating depression and other related disorders. Herein we report the implementation of extensive in-silico calculations to predict the mono-amine inhibitory potential of an in-house library of piperazine-based compounds. In this connection, a multistep virtual screening protocol based on pharmacophore modeling, molecular docking and Quantitative Structure-Activity Relationship (QSAR) was carried out by MOE. Further, to assess its ability to cross the blood brain barrier, ADME properties of the compounds were predicted. Compounds predicted the highest enzyme inhibition by QSAR was synthesized for experimental validation. Both the synthesized compounds (I15 and I21) presented good strength against Monoamine Oxidase in in vitro enzyme inhibitory activity.

1,3-di-4-piperidylpropane derivatives as potential acetyl cholinesterase antagonists: Molecular docking, synthesis, and biological evaluation.

Acetylcholine esterase (AChE) is a key biological target responsible for the management of cholinergic transmission, and its inhibitors are used for the therapy of Alzheimer's disease. In the present study, a small library of molecules with 1,3-di-4-piperidylpropane nucleus were docked on AChE. The selected compounds were synthesized and evaluated for their enzyme inhibition. P25 and P17 expressed significantly higher AChE inhibition than standards with IC50 values of 0.591µM and 0.625µM, respectively. Binding mode of derivatives in the active site of AChE revealed dual binding of molecules in peripheral anionic site (PAS) and catalytic anionic site (CAS) of enzyme cavity.

Pharmacophoric screening of newly synthesized isoniazid derivatives and their antimycobacterial activity.

Mycobacterium tuberculosis is clinically recognized as a causative agent of Tuberculosis. Keeping in view, this study was endeavored to screen our previously synthesized seventeen INH analogues for their antimycobacterial potential using proportion method. During this process, INH and all the seventeen compounds were examined at different concentrations of 0.05, 0.1 and 0.2µg/mL which were prepared using Lowenstein-Jensen (LJ) base. For drug susceptibility test, three Mycobacterial strains ATCC H37Rv, known INH-sensitive and INH-resistant strains were selected, sub-cultured on LJ Medium and serial diluted to achieve 1:10, 1:100, 1:1000 and 1:10000 from calibrated bacterial suspension Mcfarland No. 1. Dilutions of 1:100 and 1:10000 were added to drug free medium and 1:100 bacterial suspension was added to each of the test concentrations and finally incubated for 4-6 weeks at 37°C. It was observed that only compounds II and XI were active against MTb. Compounds III, IX and X also showed activity but were less potent. Ligand Scout 3.02[il_10] was used to perform pharmacophore-based screening where important pharmacophoric features were identified in the structures of these compounds which could be related to their observed antimycobacterial activity.

Synthesis, characterization and SAR of novel Bezimidazole derivatives as Nematicidal agents.

Six novel analogues were prepared by reacting benzimidazole molecules (BM and CMB) propiophenone and benzoyl chlorides respectively. The structures of newly synthesized compounds were determined with the help of spectroscopic techniques. The compounds were subjected to in-vitro screening for their activity against nematodes. It was observed that the benzimidazole (BM) derivatives possessed more nematicidal activity as compared to that of cyanomethyl-benzimidazole (CMB) for Meloidogyne incognita. Among them, the propiophenone substituted benzimidazole derivative B3 was found to be the most active compound and can be further studied as lead molecule for development of anthelmintic drugs.

Cytotoxic and acute toxicity studies of isoniazid derivatives.

Cancer is ultimately the result of cells that hysterically grow and do not die. Cells can experience uncontrolled growth if there are mutations to DNA, and therefore, alterations to the genes involved in cell division. Cancer occurs when a cell's gene mutations make the cell unable to correct DNA damage and is unable to destroy itself. There are over 100 different types of cancer each classified by the type of initially affected cell. Isoniazid, a well-known antitubercular agent has been reported to exhibit some cytotoxic activity. This finding prompt us to carry out this study where isoniazid and its sixteen derivatives were studied for any possible cytotoxic activity against Human astrocytoma SNB-19 cells, human Dukes' type C colorectal adenocarcinoma HCT-15 cells, human Dukes' type D colorectal adenocarcinoma COLO-205 cells, and human prostate adenocarcinoma (grade IV) PC-3 cells. Among the test compounds, SN-07 (a phenacyl derivative with para phenyl substitution) demonstrated slight cytotoxic effects on two types of human colorectal adenocarcinoma cells HCT-15 and COLO-205. Moreover, the acute toxicity of the compounds was also estimated in which some compounds were evaluated with more LD50 values than isoniazid.

Determination of pKa values of new phenacyl-piperidine derivatives by potentiometric titration method in aqueous medium at room temperature (25±0.5oC).

Dissociation constant (pKa) of ten novel phenacyl derivatives of piperidine were determined by potentiometric titration method in aqueous medium at room temperature (25 ±0.5°C). The sample solutions were prepared in deionized water with ionic strength 0.01M and titrated with 0.1M NaOH solution. In addition, ΔG values were also calculated. Different prediction software programs were used to calculate pKa values too and compared to the experimentally observed pKa values. The experimental and theoretical values were found in close agreement. The results obtained in this research would help to predict the good absorption of the studied compounds and can be selected as lead molecules for the synthesis of CNS active agents because of their lipophilic nature especially compound VII.

Behavioral and neurochemical profile of some novel phenacyl based isonipecotamide derivatives.

Study of natural products led to the development of new molecules of potential biological activity. Piperidine nucleus constitutes one of the components of various alkaloids and drugs. During the course of our project regarding the synthesis of derivatives of piperidine carboxamide to study the effects of these compounds as anti-depressive agents, some of the compounds exhibited significant effects at all three doses, through open field activity thus establishing a direct relationship between dose and locomotion. Moreover, these compounds have also shown the decreased level of 5-HT alone with increased level of dopamine as an indication of their antagonism towards 5-HT receptor.

Synthesis of 9-Aminoacridine Derivatives as Anti-Alzheimer Agents.

In the present study, some 9-aminoacridine derivatives have been synthesized by condensation of 9-aminoacridine with substituted phenacyl, benzoyl, and benzyl halides (RM1-RM6). Compounds were investigated for acetylcholinesterase and butyrylcholinesterase inhibition potential, considering these enzymes playing a key role in Alzheimer's disease. All derivatives showed better inhibition of enzymes than the standard galantamine, whereas except RM4, all exhibit better results than tacrine, a well-known acridine derivative used for the treatment of Alzheimer's disease.