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Background and purpose: Isatin derivatives have excited attention due to their biological attractions, especially, anticancer properties. Isatin analogs such as semaxanib and sunitinib were exposed to tyrosine kinase inhibitory properties. N-substituted isatins were reported to show cytotoxic activity. On the other, the extension of impressive and cost-effective agents against leishmaniasis is necessary in third-world countries. The capability of isatin derivatives to create novel anticancer and anti-leishmanial compounds has been identified in medicinal chemistry research. The current study aimed to synthesize N-alkyl-isatin-3-imino aromatic amine compounds and evaluate their biological effects. Experimental approach: Synthesis started with the formation of 2-chloro-N-phenylacetamide derivatives by the reaction of aniline derivatives with chloroacetyl chloride. N-alkylation of isatin was performed in the presence of K2CO3 in N, N-dimethylformamide. Final products were prepared via the condensation of N-alkyl isatin derivatives with aromatic amines. Cell viability was checked out by using the MTT assay against cancer cells. Final compounds were screened for anti-leishmanial activity. The molecules were docked in the active sites of the epidermal growth factor receptor tyrosine kinase to define the possible interactions. Findings/Results: Compounds 5c and 4d with IC50 value of 50 µM showed cytotoxic activity on the MCF-7 cell line. Compound 5b presented anti-leishmanial activity against promastigote form after 48 h (IC50:59 µM) and 72 h (IC50: 41 µM) incubations. The highest docking score was -7.33 kcal/mol for compound 4d. Conclusions and implications: The nature of substitution in the N1 region of isatin seems to be able to influence the cytotoxic activity. Based on the obtained results of docking and cytotoxic tests, compound 4d seems to be a good compound for further investigations. [ABSTRACT FROM AUTHOR]

In this study, different heterocyclic entities consisting of tyrosine amino acid and triazine ring were designed based on the structure of fingolimod, the first oral drug for multiple sclerosis (MS). Interaction of these compounds with S1P1 and S1P3, as two involving targets for fingolimod, was evaluated utilizing molecular docking and then the designed compounds were synthesized and evaluated in the terms of red blood cell and T-lymphocyte depletion in comparison to fingolimod. The 4-aminopyridine substituted derivative (8a) showed low binding energy with the active site of S1P1 (−9.4 kcal/mol) and higher binding energy (−5.87 kcal/mol) with the active site of S1P3. Also, in pharmacological studies, this compound was able to reduce white blood cells better than fingolimod and did not show destructive effects on red blood cells, unlike fingolimod. [ABSTRACT FROM AUTHOR]

Objective(s): Depression is a prevalent psychiatric disorder. Treatment of depression is still a challenge due to the lack of response of some patients to a variety of available medications and side effects. Isatin is an interesting molecule with diversified biological effects. It also participates in many synthetic reactions, as a precursor molecule. In this study, a new series of N-alkyl and N-benzyl isatin derivatives bearing Schiff bases were synthesized and screened for antidepressant activities in mice. Materials and Methods: The synthesis was initiated by N-alkylation and N-benzylation of isatin by an alkylation reaction to give N-substituted isatins. 2-(Benzyloxy) benzohydrazide derivatives were synthesized by treating methyl2-hydroxybenzoate with benzyl bromide or 4-chlorobenzyl bromide which was followed by a reaction with hydrazine hydrate to provide acid hydrazide derivatives. The final compounds were obtained by condensation of N-substituted isatins with 2-(benzyloxy) benzohydrazide derivatives as Shiff-base products. Compounds were evaluated for antidepressant activities in mice by the locomotor activity, marble burying test, and forced swimming test. Monoamine oxidase-A (MAO-A) enzyme has been used for molecular docking studies. Results: Compounds 8b and 8e in both doses, and 8 c in the lower dose, reduced immobility time during the forced swimming test relative to the control group. All preparations reduced the number of marbles buried compared with the control group. The highest docking score was -11.01 kcal/mol for compound 8e. Conclusion: N-Benzylated-isatin (8b, 8e) and N- acetic acid ethyl ester -isatin derivatives (8c) showed more effective antidepressant activity compared with N-phenyl acetamide isatin derivatives. Docking results relatively confirm the pharmacological results. [ABSTRACT FROM AUTHOR]

Background and purpose: One of the most noteworthy methods to slow down multiple sclerosis (MS) progress is a decrease of lymphocyte cells via S1P1 receptor modulating. Here, a series of S1P1 receptor modulators were designed and investigated for their ability to decrease lymphocytes in a rat model. Experimental approach: Molecular docking was performed to compare the binding mode of desired compounds 5a-f with fingolimod to the active site of the S1P1 receptor, theoretically. To prepare desired compounds, 5a-f, cyanuric chloride was reacted with different amines, a-f, which then converted to 4a-f compounds through reaction with N-boc-Tyr-OMe ester. Finally, deprotection of the carboxyl and amino groups was carried out to obtain 5a-f as final products. Lymphocyte counting in the rat model was carried out using flow cytometry to evaluate the efficacy of the suggested compounds. Findings / Results: All compounds exhibited lower binding energy than fingolimod. Compound 5e with ΔG= -8.10 kcal/mol was the best compound. The structure of the compounds was confirmed spectroscopically. The in vivo study proved that compounds 5b and 5a decreased the lymphocytes level at 0.3 and 3 mg/kg, respectively. Conclusion and implications: The desired compounds were well fitted in the receptor active site following molecular docking studies. The results of lymphocyte count revealed that compounds 5a and 5b with propyl and ethyl substitutes showed the maximum activity in vivo. Finally, the results of the present project can be used for forthcoming investigations towards the design and synthesis of novel potential agents for MS treatment. [ABSTRACT FROM AUTHOR]

Background and purpose: In this study, some new cytotoxic hybrid structures were synthesized by combining pyrazolinone and imidazolinone rings with quinazoline pharmacophores. Experimental approach: The benzoxazinone, pyrazolo-quinazoline fused ring, and imidazolinone anchored quinazoline derivatives were synthesized by simple ring-opening, ring expansion, and ring closure strategies from oxazolones. The molecular docking studies of the final derivatives were accomplished on the epidermal growth factor receptor enzyme. The cytotoxic effect of the final compounds on the MCF-7 cell line was evaluated by MTT assay. Findings/Results: The docking results confirmed the optimized electrostatic, H-bonding, and hydrophobic interactions of structures with the key residues of the active site (ΔGbin < -9Kcal/mol). The derivatives have been obtained in good yield and purity, and their structures were confirmed by different methods (FT-IR, 1H-NMR, 13C-NMR, and CHNS analysis). The IC50s of all final derivatives against the MCF-7 cell line were lower than 10 μM, and between all, the IXa from pyrazolo-quinazolinone class (IC50: 6.43 μM) with chlorine substitute was the most potent. Furthermore, all derivatives showed negligible cytotoxicity on HUVEC normal cell line which would be a great achievement for a novel cytotoxic agent. Conclusion and implications: Based on the obtained results, pyrazolo[1,5-c] quinazolin-2-one series were more cytotoxic than imidazolinone methyl quinazoline-4(3H)-ones against MCF-7 cells. Chlorine substitute in the para position of the aromatic ring improved the cytotoxicity effect in both classes. It could be related to the polarizability of a chlorine atom and making better intermolecular interactions. Further pre-clinical evaluations are required for the promising synthesized cytotoxic compounds. [ABSTRACT FROM AUTHOR]

Background and purpose: In the last few decades, nitrogen-rich heterocyclic compounds such as 1, 3, 4-thiadiazoles, 1, 2, 4-triazoles and 1, 3, 4-oxadiazoles have received considerable attention because of their notable biological properties, especially cytotoxic effects. The small molecules of mentioned azole derivatives revealed very intensive antitumor activity. In addition, phthalimide-thiadiazole and naphthalimide-triazole hybrid derivatives have shown remarkable cytotoxic effects. According to these observations, some of the hybrid derivatives containing the phthalimide-five-membered azoles were prepared in three steps in this research. Experimental approach: The thiol group of azoles was treated with ethyl chloroacetate which was followed by a reaction with hydrazine hydrate to provide acid hydrazide derivatives. Subsequently, the corresponding acid hydrazides were utilized to prepare the final derivatives through the reaction with phthalic anhydride. Cytotoxic activity of final compounds was evaluated against MCF-7 and HeLa cell lines using MTT assay. Findings/Results: Compound 3d containing two phthalimide moieties in its structure showed a significant improvement in cytotoxic activity with an IC50 value of 29 μM against HeLa cell line. Compounds 3a-3c showed less cytotoxic effects against both cell lines. Conclusion and implications: The combination of the thiadiazole nucleus with two phthalimide structures increased the cytotoxic activity against the HeLa cell line. This increase in cytotoxic activity is probably due to its being more lipophilic characteristic and interaction of this derivative with the biological targets of two directions. [ABSTRACT FROM AUTHOR]