Alireza Aliabadi

Synthesis and in-vitro cytotoxicity of poly-functionalized 4-(2-arylthiazol-4-yl)-4H-chromenes.

A new series of 4‐aryl‐4H‐chromenes bearing a 2‐arylthiazol‐4‐yl moiety at the 4‐position were prepared as potential cytotoxic agents. The in‐vitro cytotoxic activity of the synthesized 4‐aryl‐4H‐chromenes was investigated in comparison with etoposide, a well‐known anticancer drug, using MTT colorimetric assay. Among them, the 2‐(2‐chlorophenyl)thiazol‐4‐yl analog 4b showed the most potent activity against nasopharyngeal epidermoid carcinoma KB, medulloblastoma DAOY, and astrocytoma 1321N1, and compound 4d bearing a 2‐(4‐chlorophenyl)thiazol‐4‐yl moiety at the 4‐position of the chromene ring exhibited the best inhibitory activity against breast cancer cells MCF‐7, lung cancer cells A549, and colon adenocarcinoma cells SW480 with IC50 values less than 5 μM. The ability of compound 4b to induce apoptosis was confirmed in a nuclear morphological assay by DAPI staining in the KB and MCF‐7 cells.

Synthesis and biological evaluation of 2-phenylthiazole-4-carboxamide derivatives as anticancer agents

A series of substituted 2-phenylthiazole-4-carboxamide derivatives were synthesized as potential cytotoxic agents and evaluated against three human cancer cell lines including T47D (Breast cancer), Caco-2 (Colorectal cancer) and HT-29 (Colon cancer). The SAR of the arylacetamido pendent connected to the para-position of 2-phenylthiazole were explored. It was found that substitution at the 4-position by a methoxy group led to improvement of activity against Caco-2 cells while 2-methoxy substituent could maintain the high activity against HT-29 and T47D cell lines. Also, 3-fluoro analog showed good cytotoxic activity profile against all cell lines with IC(50) values less than 10 μg/mL.

SYNTHESIS, DOCKING AND ACETYLCHOLINESTERASE INHIBITORY ASSESSMENT OF 2- (2- (4-BENZYLPIPERAZIN- 1-YL) ETHYL) ISOINDOLINE-1, 3-DIONE DERIVATIVES WITH POTENTIAL ANTI-ALZHEIMER EFFECTS

BackgroundAlzheimer’s disease (AD) as neurodegenerative disorder, is the most common form of dementia accounting for about 50-60% of the overall cases of dementia among persons over 65 years of age. Low acetylcholine (ACh) concentration in hippocampus and cortex areas of the brain is one of the main reasons for this disease. In recent years, acetylcholinesterase (AChE) inhibitors like donepezil with prevention of acetylcholine hydrolysis can enhance the duration of action of acetylcholine in synaptic cleft and improve the dementia associated with Alzheimer’s disease.ResultsDesign, synthesis and assessment of anticholinesterase activity of 2-(2-(4-Benzylpiperazin-1-yl)ethyl)isoindoline-1,3-dione derivatives showed prepared compounds can function as potential acetylcholinesterase inhibitor. Among 12 synthesized derivatives, compound 4a with ortho chlorine moiety as electron withdrawing group exhibited the highest potency in these series (IC50 = 0.91 ± 0.045 μM) compared to donepezil (IC50 = 0.14 ± 0.03 μM). The results of the enzyme inhibition test (Ellman test) showed that electron withdrawing groups like Cl, F and NO2 can render the best effect at position ortho and para of the phenyl ring. But compound 4g with methoxy group at position 3(meta) afforded a favorable potency (IC50 = 5.5 ± 0.7 μM). Furthermore, docking study confirmed a same binding mode like donepezil for compound 4a.ConclusionsSynthesized compounds 4a-4l could be proposed as potential anticholinesterase agents.

Discovery of 2-Phenyl-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)acetamide Derivatives as Apoptosis Inducers via the Caspase Pathway with Potential Anticancer Activity

In the current research of medicinal chemistry, apoptosis induction is one of the novel strategies for the development and discovery of novel anticancer therapeutics. In the present study, a new series of 1,3,4‐thiadiazole derivatives (4a–4p) were synthesized and their in vitro anticancer activities were evaluated against three cancer cell lines: PC3 (prostate cancer), MCF7 (breast cancer), and SKNMC (neuroblastoma). These cell lines were utilized in MTT assays and the obtained results were compared to doxorubicin. Apoptosis induction was also investigated through exploration of the activation of caspases 3, 8, and 9. According to the obtained results, compounds 4b (3‐Cl) and 4c (4‐Cl) demonstrated the best caspase activation. In fact, compounds 4b and 4c enhanced the activity of caspases 3 and 9 in the MCF7 cell line.

Synthesis and In-Vitro Antibacterial Activity of 5-Substituted 1-Methyl-4-nitro-1H-imidazoles

A series of 5‐substituted 1‐methyl‐4‐nitro‐1H‐imidazole derivatives were synthesized and evaluated for in‐vitro antibacterial activity against a panel of microorganisms including Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, Esherichia coli, Klebsiella pneumonia, Entrobacter aerogenes, and Helicobacter pylori using conventional agar dilution method. Among the test compounds, 1‐methyl‐4‐nitro‐5‐(phenylsulfonyl)‐1H‐imidazole was the most potent against Gram‐positive bacteria, with a MIC value of ⪇8 μg/mL. All compounds showed no significant activity against Gram‐negative bacteria at concentrations ⪇64 μg/mL The MIC values against 15 clinical isolates of H. pylori indicated that compounds 10 and 11 were the most active compounds in this series in terms of inhibiting the growth of H. pylori (MIC = 2 μg/mL). It was also demonstrated that their corresponding activities were four times larger than that of metronidazole.

Design, Synthesis and Cytotoxicity Evaluation of N-(5-Benzylthio)-4H-1,2,4-Triazol-3-YL)-4-Fluorobenzamide Derivatives as Potential Anticancer Agents

Despite advances in anticancer drug development and discovery, the survival of patients is so poor. A deep need for discovery of novel anticancer drugs is among priority issues in medicinal chemistry now. A new series of 1,2,4-triazole derivatives were designed and synthesized by means of bioisosteric replacement. In vitro cytotoxicity evaluation was carried out with respect to PC3 (prostate carcinoma), HT29 (colorectal cancer) and SKNMC (neuroblastoma) cell lines using MTT assay, and the obtained results were compared to imatinib as a reference drug. Spectroscopic methods including 1H NMR, IR, and MS were used for characterization of the synthesized compounds. Generally, none of the tested compounds showed superior activity in comparison to imatinib against PC3 and SKNMC cell lines. However, compound 3b (IC50 = 3.69 ± 0.9 μM) and 3e(IC50 = 15.31 ± 2.1 μM) exhibited higher activity than imatinib (18.1 ± 2.6) against HT29 cells. Some of the obtained 1,2,4-triazole derivatives can be proposed as potential anticancer agents – in particular, against colorectal cancer – but further structural modifications and experimental tests are needed to increase the anticancer activity.

Synthesis and psychobiological evaluation of modafinil analogs in mice

Background and the purpose of the studyModafinil, a novel wake-promoting agent with low potential for abuse and dependence, has a reliable structure to find some novel derivatives with better activity and lower potential for abuse and risk of dependency. This study was designed to evaluate psychobiological activity of some novel N-aryl modafinil derivatives.MethodsSeven novel N-aryl modafinil derivatives were synthesized through three reactions: a) preparation of benzhydrylsulfanyl acetic acid through reaction of benzhydrol with thioglycolic acid, b) formation of desired amide by adding the substituted aniline to activated acid with EDC (1-ethyl-3-(3-dimethyl amino propyl) carbodiimide). This reaction was catalyzed by HOBt (N- hydroxylbenzotriazole), and c) oxidation of sulfur to sulfoxide group with H2O2. Then, their psychobiological effect on the performance of male albino mice were compared to that of modafinil as following: wakefulness by determining the effects of derivatives on phenobarbital-induced loss of the righting reflex (LOPR); exploratory activity by measuring activity in the open field test (OFT); depression by measuring immobility time (IT) during forced swimming test (FST) and the anxiogenic and anxiolytic like effects by using elevated plus-maze test (EPM). All tests were videotaped and analyzed for the frequency and duration of the behaviors during the procedures.Conclusions2-(Benzhydrylsulfonyl)-N-(4-chlorophenyl)acetamide (4c) showed comparable result in LOPR test. However, all analogs were found to be stimulant except 2-(benzhydrylsulfinyl)-N-phenylacetamide (4a). Also 4c led the most exploratory activity in mice among derivatives. FST results showed that 4a had the longest IT while modafinil, 2-(benzhydrylsulfinyl)-N-(3-chlorophenyl) acetamide (4b) and 2-(benzhydrylsulfinyl)-N-(4-ethylphenyl) acetamide (4d) had the shortest IT. In EPM, all derivatives showed anxiogenic-like behavior since they decreased open arms time and open arms entries and simultaneously increased close arms time.

Phthalimide analogs as probable 15-lipoxygenase-1 inhibitors: synthesis, biological evaluation and docking studies.

BackgroundRecent studies have been explained the role of lipoxygenases (LOX) in the origin of cancer. Among the lipoxygenases, the 5-LOX, 12-LOX and 15-LOX are more important in the cause of neoplastic disorders. In the present investigation, a new series of anticancer agents with 1,3,4-thiadiazole and phthalimide substructures were synthesized and their in vitro cytotoxicity was evaluated by MTT assay. Moreover, enzyme inhibitory potency was also assessed by enzymatic protocol towards 15-LOX-1. Molecular docking was performed to explore in silico binding mode of the target compounds.ResultsTested compounds showed a better cytotoxic activity against HT29 cell line (colorectal cancer) in comparison with other cell lines (PC3: prostate carcinoma; SKNMC: neuroblastoma). Unfortunately, all of the tested derivatives rendered lower inhibitory potency than quercetin towards 15-LOX-1. Four hydrogen bonds were detected in docking studies for compound 4d as the most potent derivative in enzymatic assay.ConclusionsThe biological results of reported compounds in this research were not so satisfactory. But, further structural modifications are necessary to improve the bioactivity of these derivatives.

2-(2-(4-Benzoylpiperazin-1-yl)ethyl)isoindoline-1,3-dione derivatives: Synthesis, docking and acetylcholinesterase inhibitory evaluation as anti-alzheimer agents

Objective(s): Alzheimer’s disease (AD) as progressive cognitive decline and the most common form of dementia is due to degeneration of the cholinergic neurons in the brain. Therefore, administration of the acetylcholinesterase (AChE) inhibitors such as donepezil is the first choice for treatment of the AD. In the present study, we focused on the synthesis and anti-cholinesterase evaluation of new donepezil like analogs. Materials and Methods: A new series of phthalimide derivatives (compounds 4a-4j) were synthesized via Gabriel protocol and subsequently amidation reaction was performed using various benzoic acid derivatives. Then, the corresponding anti-acetylcholinesterase activity of the prepared derivatives (4a-4j) was assessed by utilization of the Ellman’s test and obtained results were compared to donepezil. Besides, docking study was also carried out to explore the likely in silico binding interactions. Results: According to the obtained results, electron withdrawing groups (Cl, F) at position 3 and an electron donating group (methoxy) at position 4 of the phenyl ring enhanced the acetylcholinesterase inhibitory activity. Compound 4e (m-Fluoro, IC50 = 7.1 nM) and 4i (p-Methoxy, IC50 = 20.3 nM) were the most active compounds in this series and exerted superior potency than donepezil (410 nM). Moreover, a similar binding mode was observed in silico for all ligands in superimposition state with donepezil into the active site of acetylcholinesterase. Conclusion: Studied compounds could be potential leads for discovery of novel anti-Alzheimer agents in the future.

Synthesis and evaluation of anticonvulsant activity of (Z)-4-(2-oxoindolin-3-ylideneamino)-N-phenylbenzamide derivatives in mice

Due to resistance of some epileptic patients to the current medications and the general incidence of severe side effects of these drugs, development and discovery of novel antiepileptic drugs is crucial. Isatin-based derivatives are promising compounds as antiepileptic agents. In this study a new series of isatin-containing derivatives were synthesized via the imine formation between isatin and p-aminobenzoic acid. Subsequently, the obtained acidic compound was utilized to prepare the final amidic derivatives (4a-4l) through the reaction with various aniline derivatives. Then, their anti-seizure activity was investigated using maximal electroshock seizure (MES) as well as pentylenetetrazole (PTZ) models in mice. Neurotoxicity of target compounds was also determined by rotarod test. Tested isatin-based derivatives exhibited a favorable protection in both MES and PTZ procedures with high safety levels in neurotoxicity test. The introduced derivatives have demonstrated remarkable activity in mice and could be suggested as potential anticonvulsant lead compounds. All methoxylated derivatives (4j, 4k, 4l) showed a significant anti-seizure activity in MES model. Compounds 4j (2-OCH3) and 4l (4-OCH3) also demonstrated a potent anti-seizure activity against PTZ. Compound 4k (m-OCH3) did not induce protection towards PTZ-induced convulsion.