Pharmacophore hybridization approach to discover novel pyrazoline-based hydantoin analogs with anti-tumor efficacy

Upadhyay, Neha; Tilekar, Kalpana; Loiodice, Fulvio; Anisimova, Natalia; Спирина, Т. С.; Sokolova, Darina V.; Smirnova, G. P.; Choe, Juhui; Meyer‐Almes, Franz‐Josef; Pokrovsky, Vadim S.; Lavecchia, Antonio; Ramaa, C. S.

doi:10.1016/j.bioorg.2020.104527

Cited by 25 publications

(10 citation statements)

References 121 publications

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“…Moreover, a pyrazoline-based hydantoin analog exhibited significant antitumor activity in the HT-29 animal xenograft model. It also induced DNA damage in K562 cells and produced a significant increase of DNA double-strand breaks, which was associated with increased phosphorylation of ATM . Inspired by some multi-target anticancer 1,2,3-triazole derivatives reported by our group, the design of some 1,2,3-triazole nitrofurantoin derivatives was planned (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Inclusion of Nitrofurantoin into the Realm of Cancer Chemotherapy via Biology-Oriented Synthesis and Drug Repurposing

et al. 2023

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Structural modifications of the antibacterial drug nitrofurantoin were envisioned, employing drug repurposing and biology-oriented drug synthesis, to serve as possible anticancer agents. Eleven compounds showed superior safety in non-cancerous human cells. Their antitumor efficacy was assessed on colorectal, breast, cervical, and liver cancer cells. Three compounds induced oxidative DNA damage in cancer cells with subsequent cellular apoptosis. They also upregulated the expression of Bax while downregulated that of Bcl-2 along with activating caspase 3/7. The DNA damage induced by these compounds, demonstrated by pATM nuclear shuttling, was comparable in both MCF7 and MDA-MB-231 (p53 mutant) cell lines. Mechanistic studies confirmed the dependence of these compounds on p53-mediated pathways as they suppressed the p53–MDM2 interaction. Indeed, exposure of radiosensitive prostatic cancer cells to low non-cytotoxic concentrations of compound 1 enhanced the cytotoxic response to radiation indicating a possible synergistic effect. In vivo antitumor activity was verified in an MCF7-xenograft animal model.

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Section: Introductionmentioning

confidence: 99%

Inclusion of Nitrofurantoin into the Realm of Cancer Chemotherapy via Biology-Oriented Synthesis and Drug Repurposing

et al. 2023

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“…Another approach that has gained prominence is pharmacophore hybridization which could give a much better control on drug distribution and pharmacodynamics [14–17] . Here, individual drugs may either be conjugated through a spacer or their key pharmacophoric features integrated into a single chemical framework to achieve multi‐targeting [16,18–23] . Possible number of drug/pharmacophore combinations is quite large but logical selection of targets/pathways for co‐targeting is important to get the best therapeutic outcome.…”

Section: Introductionmentioning

confidence: 99%

Hybridization of the Pharmacophoric Features of Discoipyrrole C and Combretastatin A‐4 toward New Anticancer Leads

Kurian,

Ashtam,

Kesavan

et al. 2023

ChemMedChem

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Pharmacophore hybridization is an attractive strategy to identify new leads against multifactorial diseases such as cancer. Based on literature analysis of compounds possessing ‘vicinal diaryl’ fragment in their structure, we considered Discoipyrroles A−D and Combretastatin A‐4 (CA‐4) as possible components in hybrid design. Discoipyrrole C (Dis C) and CA‐4 were used as reference compounds in these studies and their hybrids, in the form of 4,5‐diaryl‐1H‐pyrrol‐3(2H)‐ones, were synthesized from suitable amino acid precursors though their ynone intermediates. Of these, the hybrid having exact substitution pattern as that of CA‐4 showed better potency and selectivity than Dis C, but its activity was less compared to CA‐4. This new analog disrupted interphase microtubules by inhibiting tubulin assembly by binding to the colchicine site, induced multipolar spindles, caused cell cycle block and apoptosis in HeLa cells. It also inhibited colony formation and migration of breast cancer cell lines.

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“…The spread of antibiotic-resistant pathogenic microorganisms represents a serious concern of the scientific community; therefore, the development of newer drugs with increased effect against broad strains of bacteria is imperative. Special attention has been paid to chalcones, a class of organic compounds with a broad range of biological activities, including antibacterial, antitumor, antimalarial, anti-inflammatory, and anti-HIV activities [ 1 , 2 , 3 , 4 ]. Moreover, chalcones are versatile precursors in the synthesis of numerous pharmacologically active heterocycle compounds, flavonoids, and isoflavonoids [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of New Azulene-Containing Chalcones

et al. 2022

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Azulene-containing chalcones have been synthesized via Claisen–Schmidt condensation reaction. Their chemical structure has been established by spectroscopic methods where the 1H-NMR spectra suggested that the title chalcones were geometrically pure and configured trans (J = 15 Hz). The influence of functional groups from azulene-containing chalcones on the biological activity of the 2-propen-1-one unit was investigated for the first time. This study presents optical and fluorescent investigations, QSAR studies, and biological activity of 10 novel compounds. These chalcones were evaluated for their antimicrobial activity against Gram-positive and Gram-negative bacteria. The results revealed that most of the synthesized compounds showed inhibition against Gram-negative microorganisms, independent of the substitution of azulene scaffold. Instead, all azulene-containing chalcones exhibited good antifungal activity against Candida parapsilosis, with MIC values ranging between 0.156 and 0.312 mg/mL. The most active compound was chalcone containing azulene moieties on both sides of the 2-propene-1-one bond, exhibiting good activity against both bacteria-type strains and good antifungal activity. This antifungal activity combined with low toxicity makes azulene-containing chalcones a new class of bioorganic compounds.

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Pharmacophore hybridization approach to discover novel pyrazoline-based hydantoin analogs with anti-tumor efficacy

Cited by 25 publications

References 121 publications

Inclusion of Nitrofurantoin into the Realm of Cancer Chemotherapy via Biology-Oriented Synthesis and Drug Repurposing

Inclusion of Nitrofurantoin into the Realm of Cancer Chemotherapy via Biology-Oriented Synthesis and Drug Repurposing

Hybridization of the Pharmacophoric Features of Discoipyrrole C and Combretastatin A‐4 toward New Anticancer Leads

Design, Synthesis, and Biological Evaluation of New Azulene-Containing Chalcones

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