Current scenario of pyrazole hybrids with in vivo therapeutic potential against cancers

Chemotherapeutics occupy a pivotal role in the medication of different types of cancers, but the prevalence and mortality rates of cancer remain high. The drug resistance and low specificity of current available chemotherapeutics are the main barriers for the effective cancer chemotherapy, evoking an immediate need for the development of novel anticancer agents. Pyrazole is a highly versatile five-membered heterocycle with two adjacent nitrogen atoms and possesses remarkable therapeutic effects and robust pharmacological potency. The pyrazole derivatives especially pyrazole hybrids have demonstrated potent in vitro and in vivo efficacies against cancers through multiple mechanisms, inclusive of apoptosis induction, autophagy regulation, and cell cycle disruption. Moreover, several pyrazole hybrids such as crizotanib (pyrazole-pyridine hybrid), erdafitinib (pyrazole-quinoxaline hybrid) and ruxolitinib (pyrazole-pyrrolo [2,3-d]pyrimidine hybrid) have already been approved for the cancer therapy, revealing that pyrazole hybrids are useful scaffolds to develop novel anticancer agents. The purpose of this review is to summarize the current scenario of pyrazole hybrids with potential in vivo anticancer efficacy along with mechanisms of action, toxicity, and pharmacokinetics, covering papers published in recent 5 years (2018-present), to facilitate further rational exploitation of more effective candidates.

 

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Title: Pyrazole Hybrids: Promising Anticancer Agents with Diverse Mechanisms of Action

Abstract: Chemotherapeutics play a crucial role in the treatment of various cancers, but the high prevalence and mortality rates of cancer necessitate the development of novel anticancer agents. Pyrazole, a versatile five-membered heterocycle with two adjacent nitrogen atoms, has shown remarkable therapeutic effects and robust pharmacological potency. In particular, pyrazole hybrids have exhibited potent in vitro and in vivo efficacies against cancers through multiple mechanisms, including apoptosis induction, autophagy regulation, and cell cycle disruption. Several pyrazole hybrids, such as crizotanib (pyrazole-pyridine hybrid), erdafitinib (pyrazole-quinoxaline hybrid), and ruxolitinib (pyrazole-pyrrolo[2,3-d]pyrimidine hybrid), have already been approved for cancer therapy, highlighting the utility of pyrazole hybrids as scaffolds for developing novel anticancer agents. This review aims to summarize the current state of pyrazole hybrids with potential in vivo anticancer efficacy, including their mechanisms of action, toxicity, and pharmacokinetics, focusing on papers published in the last five years (2018-present). The findings of this review will facilitate the rational exploitation of more effective pyrazole hybrid candidates for cancer treatment.

1. Introduction
   - Challenges in cancer chemotherapy
   - Importance of developing novel anticancer agents

2. Pyrazole and its Therapeutic Potential
   - Overview of pyrazole as a versatile heterocycle
   - Remarkable therapeutic effects and pharmacological potency

3. Mechanisms of Action of Pyrazole Hybrids in Cancer Therapy
   - Apoptosis induction
   - Autophagy regulation
   - Cell cycle disruption
   - Other mechanisms of action

4. Approved Pyrazole Hybrid Anticancer Agents
   - Crizotanib: A pyrazole-pyridine hybrid
   - Erdafitinib: A pyrazole-quinoxaline hybrid
   - Ruxolitinib: A pyrazole-pyrrolo[2,3-d]pyrimidine hybrid

5. Recent Advances in Pyrazole Hybrid Anticancer Agents
   - In vitro and in vivo efficacies
   - Mechanistic insights
   - Toxicity evaluation

6. Pharmacokinetics of Pyrazole Hybrids
   - Absorption, distribution, metabolism, and excretion
   - Pharmacokinetic studies and considerations

7. Conclusion and Future Perspectives
   - Summary of current scenario of pyrazole hybrids in anticancer therapy
   - Potential for further rational exploitation and development of more effective candidates

By reviewing the recent literature on pyrazole hybrids, this article aims to provide a comprehensive overview of their potential as anticancer agents. Understanding their mechanisms of action, toxicity profiles, and pharmacokinetics will facilitate the identification and development of more effective pyrazole hybrid candidates for future cancer therapies.

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