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Exploration of 1,3,5-trisubstituted pyrazoline derivatives as human carbonic anhydrase inhibitors: Synthesis,
Danaboina Srikanth1, Kollu Shanthi1, Niccolò Paoletti2
1Department of Chemical Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.
Abstract:
The human carbonic anhydrase (hCA) IX and XII isoforms are overexpressed in hypoxic conditions, contributing to cancer. Lack of isoform selectivity has been one of the main challenges associated with the existing drugs targeting hCAs. Hence, the development of alternative approaches, such as tail approach to develop more selective hCA IX and XII inhibitors is need of the hour. In the present work, we designed and synthesized 24 new 1,3.5-trisubstituted-pyrazoline derivatives with diverse substitutions. The synthesized analogs were evaluated for their hCA inhibitory activities against hCA I, II, IX, and XII isoforms. Among the tested compounds, derivative 8 displayed good inhibitory activity against hCA IX (Ki = 331 nM) and XII (Ki = 96.7 nM). In addition, 9a-g also exhibited some inhibitory activities against hCA IX and XII, with Kis ranging from 574-799 nM and 137-369 nM, respectively. Molecular modelling studies of compound 8 displayed metal coordination with zinc ion and hydrophobic, hydrophilic interactions with adjacent amino acid residues, and maintained stable interactions throughout 100 ns. In addition, ADMET studies demonstrated that compound 8 obeyed the Lipinski's rule of five and was found to be druggable and non-toxic. Hence, compound 8 was identified as potential lead for further development.
Insights
Researchers developed novel pyrazoline derivatives to selectively inhibit human carbonic anhydrase (hCA) IX and XII, crucial in cancer. Compound 8 showed promising inhibitory activity and druggability, offering a potential lead for cancer therapy.
Area of Science:
- Medicinal Chemistry
- Biochemistry
- Cancer Research
Background:
- Human carbonic anhydrase (hCA) IX and XII are overexpressed in hypoxic tumors, promoting cancer progression.
- Existing hCA inhibitors lack isoform selectivity, posing a therapeutic challenge.
- Targeting hCA IX and XII specifically is crucial for developing effective cancer treatments.
Purpose of the Study:
- To design and synthesize novel 1,3,5-trisubstituted-pyrazoline derivatives.
- To evaluate the inhibitory activity of these derivatives against hCA isoforms I, II, IX, and XII.
- To identify selective inhibitors of hCA IX and XII for potential cancer therapy.
Main Methods:
- Synthesis of 24 new 1,3,5-trisubstituted-pyrazoline derivatives.
- In vitro evaluation of hCA inhibitory activities against hCA I, II, IX, and XII.
- Molecular modeling and ADMET studies for lead compound characterization.
Main Results:
- Derivative 8 exhibited potent inhibition against hCA IX (Ki = 331 nM) and hCA XII (Ki = 96.7 nM).
- Derivatives 9a-g also showed inhibitory activity against hCA IX and XII.
- Compound 8 demonstrated favorable druggability and non-toxicity through ADMET and Lipinski's rule of five analysis.
- Molecular modeling confirmed stable interactions of compound 8 with the hCA active site.
Conclusions:
- Compound 8 is a promising lead compound for developing selective hCA IX and XII inhibitors.
- The developed pyrazoline derivatives offer a novel approach for targeting cancer-associated carbonic anhydrases.
- Further development of compound 8 could lead to new therapeutic strategies for hypoxic cancers.
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