Design, synthesis and evaluation of 2-(4-(substituted benzoyl)-1,4-diazepan-1-yl)-N-phenylacetamide derivatives as a new class of falcipain-2 inhibitors
The cysteine protease, falcipain-2 is an important drug target in human malaria parasite Plasmodium falciparum. A new series of 2-(4-(substituted benzoyl)-1,4-diazepan-1-yl)-N-phenylacetamide derivatives 5(a–t) were designed as per pharmacophoric requirements of falcipain-2 inhibitors using ligand-b...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-11-01
|
| Series: | Arabian Journal of Chemistry |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1878535214002561 |
| _version_ | 1818669332382613504 |
|---|---|
| author | Radhakrishnan Mahesh Sourabh Mundra Thangaraj Devadoss Lakshmi P. Kotra |
| author_facet | Radhakrishnan Mahesh Sourabh Mundra Thangaraj Devadoss Lakshmi P. Kotra |
| author_sort | Radhakrishnan Mahesh |
| collection | DOAJ |
| description | The cysteine protease, falcipain-2 is an important drug target in human malaria parasite Plasmodium falciparum. A new series of 2-(4-(substituted benzoyl)-1,4-diazepan-1-yl)-N-phenylacetamide derivatives 5(a–t) were designed as per pharmacophoric requirements of falcipain-2 inhibitors using ligand-based approach. The target compounds were synthesized from the key intermediate, 2-(1,4-Diazepan-1-yl)-N-phenylacetamide, by coupling it with appropriate carboxylic acids using carbodiimide chemistry. Structural features of target compounds were characterized by spectral data (1H NMR, and mass) and elemental analyses. The purity of the final compounds was confirmed by HPLC. The compounds were tested for their in vitro falcipain-2 inhibitor activity on recombinant falcipain-2 enzyme. Five compounds 5b, 5g, 5h, 5j, 5k showed good inhibitory activity (>60%), against falcipain-2 at 10 μM concentration, and fifteen compounds showed weak to moderate inhibitor activity. Compound 5g, the most potent compound from this series showed 72% inhibition at 10 μM concentrations. Keywords: Malaria, Plasmodium falciparum, Structure–activity relationships (SARs), Ligand-based drug design, Antimalarial agents |
| first_indexed | 2024-12-17T06:50:32Z |
| format | Article |
| id | doaj.art-26c6809e30414cb3a1a9d1ca08cfd0ae |
| institution | Directory Open Access Journal |
| issn | 1878-5352 |
| language | English |
| last_indexed | 2024-12-17T06:50:32Z |
| publishDate | 2019-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Arabian Journal of Chemistry |
| spelling | doaj.art-26c6809e30414cb3a1a9d1ca08cfd0ae2022-12-21T21:59:36ZengElsevierArabian Journal of Chemistry1878-53522019-11-0112714361446Design, synthesis and evaluation of 2-(4-(substituted benzoyl)-1,4-diazepan-1-yl)-N-phenylacetamide derivatives as a new class of falcipain-2 inhibitorsRadhakrishnan Mahesh0Sourabh Mundra1Thangaraj Devadoss2Lakshmi P. Kotra3Department of Pharmacy, FD-3, Birla Institute of Technology & Science, Pilani 333031, Rajasthan, IndiaDepartment of Pharmacy, FD-3, Birla Institute of Technology & Science, Pilani 333031, Rajasthan, India; Corresponding author at: Department of Pharmacy, FD-3, Birla Institute of Technology & Science, Pilani 333031, Rajasthan, India. Fax: +91 01596244183.Department of Pharmacy, FD-3, Birla Institute of Technology & Science, Pilani 333031, Rajasthan, IndiaCentre for Molecular Design and Preformulations, University Health Network, Toronto, CanadaThe cysteine protease, falcipain-2 is an important drug target in human malaria parasite Plasmodium falciparum. A new series of 2-(4-(substituted benzoyl)-1,4-diazepan-1-yl)-N-phenylacetamide derivatives 5(a–t) were designed as per pharmacophoric requirements of falcipain-2 inhibitors using ligand-based approach. The target compounds were synthesized from the key intermediate, 2-(1,4-Diazepan-1-yl)-N-phenylacetamide, by coupling it with appropriate carboxylic acids using carbodiimide chemistry. Structural features of target compounds were characterized by spectral data (1H NMR, and mass) and elemental analyses. The purity of the final compounds was confirmed by HPLC. The compounds were tested for their in vitro falcipain-2 inhibitor activity on recombinant falcipain-2 enzyme. Five compounds 5b, 5g, 5h, 5j, 5k showed good inhibitory activity (>60%), against falcipain-2 at 10 μM concentration, and fifteen compounds showed weak to moderate inhibitor activity. Compound 5g, the most potent compound from this series showed 72% inhibition at 10 μM concentrations. Keywords: Malaria, Plasmodium falciparum, Structure–activity relationships (SARs), Ligand-based drug design, Antimalarial agentshttp://www.sciencedirect.com/science/article/pii/S1878535214002561 |
| spellingShingle | Radhakrishnan Mahesh Sourabh Mundra Thangaraj Devadoss Lakshmi P. Kotra Design, synthesis and evaluation of 2-(4-(substituted benzoyl)-1,4-diazepan-1-yl)-N-phenylacetamide derivatives as a new class of falcipain-2 inhibitors Arabian Journal of Chemistry |
| title | Design, synthesis and evaluation of 2-(4-(substituted benzoyl)-1,4-diazepan-1-yl)-N-phenylacetamide derivatives as a new class of falcipain-2 inhibitors |
| title_full | Design, synthesis and evaluation of 2-(4-(substituted benzoyl)-1,4-diazepan-1-yl)-N-phenylacetamide derivatives as a new class of falcipain-2 inhibitors |
| title_fullStr | Design, synthesis and evaluation of 2-(4-(substituted benzoyl)-1,4-diazepan-1-yl)-N-phenylacetamide derivatives as a new class of falcipain-2 inhibitors |
| title_full_unstemmed | Design, synthesis and evaluation of 2-(4-(substituted benzoyl)-1,4-diazepan-1-yl)-N-phenylacetamide derivatives as a new class of falcipain-2 inhibitors |
| title_short | Design, synthesis and evaluation of 2-(4-(substituted benzoyl)-1,4-diazepan-1-yl)-N-phenylacetamide derivatives as a new class of falcipain-2 inhibitors |
| title_sort | design synthesis and evaluation of 2 4 substituted benzoyl 1 4 diazepan 1 yl n phenylacetamide derivatives as a new class of falcipain 2 inhibitors |
| url | http://www.sciencedirect.com/science/article/pii/S1878535214002561 |
| work_keys_str_mv | AT radhakrishnanmahesh designsynthesisandevaluationof24substitutedbenzoyl14diazepan1ylnphenylacetamidederivativesasanewclassoffalcipain2inhibitors AT sourabhmundra designsynthesisandevaluationof24substitutedbenzoyl14diazepan1ylnphenylacetamidederivativesasanewclassoffalcipain2inhibitors AT thangarajdevadoss designsynthesisandevaluationof24substitutedbenzoyl14diazepan1ylnphenylacetamidederivativesasanewclassoffalcipain2inhibitors AT lakshmipkotra designsynthesisandevaluationof24substitutedbenzoyl14diazepan1ylnphenylacetamidederivativesasanewclassoffalcipain2inhibitors |