Success stories of natural product-based hybrid molecules for multi-factorial diseases

Choudhary, Shalki; Singh, Pankaj Kumar; Verma, Himanshu; Singh, Harpreet; Silakari, Om

doi:10.1016/j.ejmech.2018.03.057

Cited by 68 publications

(75 citation statements)

References 183 publications

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“…Hybrid molecules, featuring two or more potentially bioactive pharmacophores, have been reported to synergistically block different pathways, which contribute in the pathogenesis of complex diseases. [56,57] Thus, indole hybrids are a useful platform for the nitro group was beneficial for the activity. [58] Two hybrids 16a,b (IC 50 :…”

Section: Indole Hybridsmentioning

confidence: 99%

The antimalarial activity of indole alkaloids and hybrids

Sun

et al. 2020

Archiv der Pharmazie

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Malaria, caused by the genus Plasmodium, remains a global public health concern. It is estimated by the World Health Organization that over 40% of the world's population lives in areas at risk for malarial transmission, and around half a million people succumb to this infectious disease annually, which is related to the rapid spread of drug-resistant parasite strains. Indole derivatives, which possess broadspectrum pharmacological properties, play a crucial role in the discovery of new drugs. Many indole derivatives exhibited potential in vitro and in vivo activity against both drug-sensitive and drug-resistant malaria, suggesting that the indole moiety is a useful template for the development of novel antimalarial agents.

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Section: Indole Hybridsmentioning

confidence: 99%

The antimalarial activity of indole alkaloids and hybrids

Sun

et al. 2020

Archiv der Pharmazie

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“…In addition, the development of multitarget hybrids based on well‐known bioactive molecules is becoming a widely used strategy in Medicinal Chemistry . Complex compounds presenting different scaffolds can be especially interesting when searching for new therapeutic solutions for multifactorial diseases, as Parkinson's disease …”

Section: Introductionmentioning

confidence: 99%

“…[8,9] Complex compounds presenting different scaffolds can be especially interesting when searching for new therapeutic solutions for multifactorial diseases, [10,11] as Parkinson's disease. [12,13] Coumarins are ubiquitous in nature and have relevant pharmacological properties such as anti-inflammatory, antioxidant and cardioprotective effects, depending on their substitution patterns. [14] Different research groups, including ours, have shown that coumarin is a privileged scaffold for the rational discovery and development of new hMAO-B inhibitors (Figure 1) and antioxidant agents.…”

Section: Introductionmentioning

confidence: 99%

Coumarin‐Rasagiline Hybrids as Potent and Selective hMAO‐B Inhibitors, Antioxidants, and Neuroprotective Agents

et al. 2020

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The frequency, complexity and morbidity of neurodegenerative diseases make them a great challenge for nowadays medicine. Most of the treatments currently used for Parkinson's disease – the second most prevalent – are only symptomatic. Therefore, it is urgent to develop drugs that are able to act simultaneously on different targets, being able to stop neuronal death and promote the recovery of neuronal populations already affected. In this work, we studied the activity of a series of hybrid molecules, which combine the structure of both coumarin and an alkynylamine group inspired on rasagiline, as MAO inhibitors, antioxidants and neuroprotective agents. Half of the studied hybrids turned out to be selective monoamine oxidase B (hMAO‐B) inhibitors in the low micro/nanomolar range, demonstrating that positions 3 (compounds 1–3) and 7 (compounds 8 and 10) of the coumarin scaffold are the most suitable for the incorporation of the alkynylamine chain. All the studied compounds proved to be capable of neutralizing free radicals (DPPH). Finally, the 4‐(but‐2‐yn‐1‐ylamino)coumarin (5) showed neuroprotective effects on glial cells and the 4‐methyl‐7‐(pent‐2‐yn‐1‐ylamino)coumarin (8) inhibited intraneuronal ROS production as well.

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“…Thus, 7- and 13-azapros- tanoids and their homo analogues [ 22 ], synthesized on the base of 2-acylcycloalkane-1,3-diones, exhibit anti-ulcerative, anti-arrhythmic and anti-ischemic activities [ 23 , 24 ]. Molecular hybridization is an effective strategy to enhance the biological activity of new molecules [ 25 , 26 ]. Keeping in view the fact that triterpenoids and azaprostanoids have different targets of anti-inflammatory effect, we supposed their hybridization could improve the pharmacological activities of the compounds.…”

Section: Introductionmentioning

confidence: 99%

Betulinic Acid-Azaprostanoid Hybrids: Synthesis and Pharmacological Evaluation as Anti-inflammatory Agents

Khlebnicova

Piven

Лахвич

et al. 2020

AIAAMC

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Background: Prevention and treatment of chronic inflammatory diseases requires effective and low-toxic medicines. Molecular hybridization is an effective strategy to enhance the biological activity of new compounds. Triterpenoid scaffolds are in the focus of attention owing to their anti-inflammatory, antiviral, antiproliferative, immunomodulatory activities. Heteroprostanoids have different pleiotropic effects in acute and chronic inflammatory processes. Objective: Development of structurally new and low toxic anti-inflammatory agents via hybridization of betulinic acid with azaprostanoic acids. Methods: A series of betulinic acid−azaprostanoid hybrids was synthesized. The synthetic pathway included a transformation of betulin via Jones' oxidation into betulonic acid, a reductive amination of the latter and coupling obtained 3β-amino-3-deoxybetulinic acid with the 7- or 13-azaprostanoic acids and their homo analogues. The hybrids 1-9 were investigated in vivo on histamine-, formalin- and concanavalin A-induced mouse paw edema models and two models of a pain ̶ the acetic acid-induced abdominal writhing and the hot-plate test. The hybrids were in vitro evaluated for cytotoxic activity on cancer (MCF7, U−87 MG) and non-cancer humane cell lines. Results: In the immunogenic inflammation model, the substances showed pronounced anti-inflammatory effect, which was comparable to that of indomethacin. In the models of the exudative inflammation, none of the compounds displayed a statistically significant effect. The hybrids produced weak or moderate analgesic effects. All agents revealed low cytotoxicity on human immortalized fibroblasts and cancer cell lines compared with 3β-amino-3-deoxybetulinic acid and doxorubicin. Conclusion: The results indicate that the principal anti-inflammatory effect of hybrids is substantially provided with the triterpenoid scaffold and in some measure with the azaprostanoid scaffold, but the last one makes a significant contribution to reducing the toxicity of hybrids. Hybrid 1 is of interest as a potent low toxic agent against immune-mediated inflammation.

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Success stories of natural product-based hybrid molecules for multi-factorial diseases

Cited by 68 publications

References 183 publications

The antimalarial activity of indole alkaloids and hybrids

The antimalarial activity of indole alkaloids and hybrids

Coumarin‐Rasagiline Hybrids as Potent and Selective hMAO‐B Inhibitors, Antioxidants, and Neuroprotective Agents

Betulinic Acid-Azaprostanoid Hybrids: Synthesis and Pharmacological Evaluation as Anti-inflammatory Agents

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