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1.
J Biomol Struct Dyn ; 40(23): 12592-12607, 2022.
Article in English | MEDLINE | ID: mdl-34488559

ABSTRACT

Leishmaniasis is one of today's most neglected diseases. The emergence of new anti-leishmanial therapies emphasizes several study groups funded by the World Health Organization. The present investigation will focus on the research to determine a few new potential derivatives of ß-carboline ester derivatives against leishmaniasis. The in-silico predicted ADMET properties of most of the titled compounds are in an acceptable range and having drug like properties. Among all the tested analogs, compound ES-3 (EC50 3.36 µM; SI > 29.80) showed comparable and equipotent anti-leishmanial activity as that of standard drug miltefosine (EC50 4.80 µM; SI > 20.80) against amastigote forms of the tested L. infantum strain. Two compounds ES-6 and ES-10 exhibited significant activity with EC50 10.16, 13.56 µM; SI > 4.90, 7.37, respectively. In-silico based molecular docking and dynamics study of the significantly active analog also performed to study the putative binding mode, interaction pattern at the active site of the target leishmanial trypanothione reductase enzyme as well as stability of the target-ligand complex. The changes in the conformation of molecules during MD (frame wise trajectory analysis) provided new insights for the development of novel potent molecules. These findings will further give insight that will help modify the compound ES-3 for better potency and the design of novel inhibitors for leishmaniasis.Communicated by Ramaswamy H. Sarma.


Subject(s)
Antiprotozoal Agents , Leishmania , Leishmaniasis , Humans , Molecular Docking Simulation , Carbolines/pharmacology , Carbolines/chemistry , Leishmaniasis/drug therapy , Molecular Conformation , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry
2.
Org Biomol Chem ; 19(48): 10601-10610, 2021 12 15.
Article in English | MEDLINE | ID: mdl-34859806

ABSTRACT

A two-pot synthesis of 5-aza-indoles has been developed from aqueous succinaldehyde and N-aryl propargylic-imines. This overall protocol involves: (i) the metal-free [3 + 2] annulation of aqueous succinaldehyde and N-aryl propargylic-imines to access 2-alkynyl-pyrrole-3-aldehydes and (ii) Ag-catalyzed 6-endo-dig-cyclization to obtain substituted 5-aza-indoles in the second pot. The 5-aza-indoles showed engaging photophysical activities, and the practicality of this pot-economic gram-scale synthesis has been demonstrated.

3.
Bioorg Med Chem Lett ; 30(16): 127304, 2020 08 15.
Article in English | MEDLINE | ID: mdl-32631524

ABSTRACT

A new series of 1,2,3-triazole tethered chalcone acetamide derivatives (7a-c &8a-r) have been synthesized in excellent yields and their structures were determined by analytical and spectral (FT-IR, 1H NMR, 13C NMR & HRMS) studies. The newly synthesized derivatives were evaluated for their cytotoxic activity against four human cancer cell lines, such as HeLa (Human cervical cancer), A549 (Human alveolar adenocarcinoma), MCF-7 (Human breast adenocarcinoma) and SKNSH (Human brain cancer). Among them, compound 7c exhibited good anti-proliferation activity with HeLa (IC50 7.41 + 0.8 µM), SKNSH (IC50 8.68 + 1.1 µM), MCF-7 (IC50 9.76 + 1.3 µM) and MDA-MB-231, while compounds 7a and 7b showed promising anti-proliferation against above four human cancer cell lines with IC50 7.95-11.62 µM, respectively, compared with the standard drug Doxorubicin. We explored the probable key active site and binding mode interactions in HDAC8 (PDB ID:3SFH) and EHMT2 (PDB ID:3K5K) proteins. The docking results are complementary to the experimental observations.


Subject(s)
Acetamides/pharmacology , Antineoplastic Agents/pharmacology , Chalcone/pharmacology , Triazoles/pharmacology , Acetamides/chemical synthesis , Acetamides/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Chalcone/chemical synthesis , Chalcone/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry
4.
Org Biomol Chem ; 18(6): 1155-1164, 2020 02 14.
Article in English | MEDLINE | ID: mdl-31976504

ABSTRACT

A simple and straightforward method for the synthesis of 4-iodo and 5-iodopyrrole-3-carboxaldehydes is developed from a common set of starting materials by tuning the reaction conditions. This sequential multicomponent protocol involves I2-mediated regioselective C4-iodination and aromatization of intermediate dihydropyrrole, generated through proline-catalyzed direct Mannich reaction-cyclization sequence between succinaldehyde and imines, to access 4-iodopyrroles. While aerobic oxidative aromatization of dihydropyrrole to pyrrole followed by NIS-mediated regioselective iodination furnished 5-iodopyrroles in a two-pot fashion. A series of site-selective C4/C5-iodopyrroles have been synthesized in good to high yields (up to 78%) and DFT calculations of these compounds were also performed.

5.
RSC Adv ; 9(42): 24050-24056, 2019 Aug 02.
Article in English | MEDLINE | ID: mdl-35527913

ABSTRACT

An efficient protocol for the synthesis of 2,2-disubstituted indolin-3-ones under mild conditions has been developed. This reaction involves the copper-catalyzed in situ oxidative de-aromatization of 2-arylindoles to indol-3-one, followed by self-dimerization as well as cross-addition with indoles under mild conditions. The result generates a wide variety of C2-tetrasubstituted indolin-3-ones with good to high yields (62-82%).

6.
Eur J Med Chem ; 69: 817-22, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24113366

ABSTRACT

A novel series of building blocks consisting of benzo[4,5]thiazolo[1,2-a]pyrimidine-3-carboxylate have been synthesized as potential anticancer compounds. These compounds were prepared from 2-aminobenzothiazole, benzaldehyde and ethyl acetoacetate in ethylene glycol by catalysing with TBAHS to give benzo[4,5]thiazo[1,2-a]pyrimidine derivative 4 followed by the formation of amide by reaction with several secondary amines in good yields. The cytotoxicity of these compounds was evaluated against human cancer cell lines in vitro (A549, HeLa, MDA-MB-231 and MCF-7). Compound 5b exhibited promising cytotoxicity with IC50 values of 0.58 and 1.58 µM specifically against human breast adenocarcinoma cell lines, MCF-7 and MDA-MB-231, while compound 5a showed promising cytotoxicity against MDA-MB-231 (IC50 value of 5.01 µM).


Subject(s)
Antineoplastic Agents/pharmacology , Benzothiazoles/pharmacology , Pyrimidines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzothiazoles/chemical synthesis , Benzothiazoles/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HeLa Cells , Humans , MCF-7 Cells , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship
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