- Amide derivatives of 4-azaindole: Design, synthesis, and EGFR targeting anticancer agents
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A series of amide derivatives of azaindole-oxazoles (11a–n) were designed and synthesized and their structures were confirmed by 1HNMR, 13CNMR and mass spectral analysis. Further, these derivatives were screened for their anticancer activity against human cancer cell lines viz; MCF7 (breast), A549 (lung) and A375 (melanoma). In vitro anticancer activity screening indicated that most of the hybrids exhibited potent inhibitory activities in a variety of cancer cell lines. Among the compounds 11d, 11e, 11f, 11j, 11k, 11l, 11m, and 11n were exhibited more potent activity than standard, in those mainly two compounds 11m and 11j were exhibited excellent activity in MCF-7 cell line with IC50 values 0.034 and 0.036 μM. Moreover, all these compounds were carried out their molecular docking studies on EGFR receptor results indicated that two potent compounds 11m and 11j were strongly binds to protein EGFR (PDB ID: 4hjo). It was found that the energy calculations were in good agreement with the observed IC50 values.
- Venkat Swamy, Puli,Kiran Kumar, Vukoti,Radhakrishnam Raju, Ruddarraju,Venkata Reddy, Regalla,Chatterjee, Anindita,Kiran, Gangarapu,Sridhar, Gattu
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- Exploration of nitrogen heterocycle scaffolds for the development of potent human neutrophil elastase inhibitors
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Human neutrophil elastase (HNE) is a potent protease that plays an important physiological role in many processes but is also involved in a variety of pathologies that affect the pulmonary system. Thus, compounds able to inhibit HNE proteolytic activity could represent effective therapeutics. We present here a new series of pyrazolopyridine and pyrrolopyridine derivatives as HNE inhibitors designed as modifications of our previously synthesized indazoles and indoles in order to evaluate effects of the change in position of the nitrogen and/or the insertion of an additional nitrogen in the scaffolds on biological activity and chemical stability. We obtained potent HNE inhibitors with IC50 values in the low nanomolar range (10–50 nM), and some compounds exhibited improved chemical stability in phosphate buffer (t1/2 > 6 h). Molecular modeling studies demonstrated that inhibitory activity was strictly dependent on the formation of a Michaelis complex between the OH group of HNE Ser195 and the carbonyl carbon of the inhibitor. Moreover, in silico ADMET calculations predicted that most of the new compounds would be optimally absorbed, distributed, metabolized, and excreted. Thus, these new and potent HNE inhibitors represent novel leads for future therapeutic development.
- Cantini, Niccolò,Khlebnikov, Andrei I.,Crocetti, Letizia,Schepetkin, Igor A.,Floresta, Giuseppe,Guerrini, Gabriella,Vergelli, Claudia,Bartolucci, Gianluca,Quinn, Mark T.,Giovannoni, Maria Paola
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