Synthesis, antimalarial activity, and target binding of dibenzazepine-tethered isoxazolines

Koravangala S. Vinay Kumar, Gejjalagere S. Lingaraju, Yadaganahalli K. Bommegowda, Ajjampura C. Vinayaka, Pritesh Bhat, Challanayakanahally S. Pradeepa Kumara, Kanchugarakoppal S. Rangappa, D. Channe Gowda, Maralinganadoddi P. Sadashiva

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Malaria, a complex and deadly parasitic infectious disease, is a huge public health problem in many endemic countries around the globe. The prevailing extensive resistance of malaria parasites to traditional drugs and emergence of resistance to the currently used frontline artemisinin-based chemotherapy calls for the development of new drugs. Towards this objective and since compounds containing the dibenzazepine moiety are effective in treating both gametocyte and asexual stage malaria parasites, including multi drug resistant parasites, a library of dibenzazepine tethered 3,5-disubstituted isoxazolines was synthesised via 1,3-dipolar cycloaddition reaction. An additional diversified group of dibenzazepine derivatives were accessed by Suzuki coupling of one of the above dibenzazepine derivatives with various organoboronic acids. All compounds were structurally characterized and were evaluated for their antimalarial activity. They exhibited good to excellent inhibitory activity against the growth of drug-sensitive Plasmodium falciparum 3D7 strain with IC50 values ranging from 0.2 to 7.7 μM. About 50% of the compounds were either minimally or not toxic to human cell lines. Five of the compounds (6j, 6k, 8c, 8k and 8l) that highly inhibited the parasite growth were further assessed for antimalarial activity using an additional chloroquine-sensitive (D6) and two chloroquine-resistant (W2 and 7G8) P. falciparum strains. These compounds were effective against all four strains (3D7, D6, W2 and 7G8), exhibiting IC50 values of 0.1 to 1.75 μM. The dibenzazepines were identified to target the metalloamino-peptidase of parasites. Molecular docking and dynamics simulation studies were performed to understand the binding mode and binding strengths of the selected compounds with the enzyme. In agreement with their excellent antimalarial activity, the data suggested that the compounds can strongly bind to the active site of the enzyme.

Original languageEnglish (US)
Pages (from-to)90408-90421
Number of pages14
JournalRSC Advances
Volume5
Issue number110
DOIs
StatePublished - Jan 1 2015

Fingerprint

Antimalarials
Chloroquine
Dibenzazepines
Pharmaceutical Preparations
Enzymes
Derivatives
Chemotherapy
Cycloaddition
Poisons
Public health
Medical problems
Peptide Hydrolases
Cells
dibenzazepine
Parasites
Acids
Computer simulation

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)

Cite this

Vinay Kumar, K. S., Lingaraju, G. S., Bommegowda, Y. K., Vinayaka, A. C., Bhat, P., Pradeepa Kumara, C. S., ... Sadashiva, M. P. (2015). Synthesis, antimalarial activity, and target binding of dibenzazepine-tethered isoxazolines. RSC Advances, 5(110), 90408-90421. https://doi.org/10.1039/c5ra17926b
Vinay Kumar, Koravangala S. ; Lingaraju, Gejjalagere S. ; Bommegowda, Yadaganahalli K. ; Vinayaka, Ajjampura C. ; Bhat, Pritesh ; Pradeepa Kumara, Challanayakanahally S. ; Rangappa, Kanchugarakoppal S. ; Gowda, D. Channe ; Sadashiva, Maralinganadoddi P. / Synthesis, antimalarial activity, and target binding of dibenzazepine-tethered isoxazolines. In: RSC Advances. 2015 ; Vol. 5, No. 110. pp. 90408-90421.
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abstract = "Malaria, a complex and deadly parasitic infectious disease, is a huge public health problem in many endemic countries around the globe. The prevailing extensive resistance of malaria parasites to traditional drugs and emergence of resistance to the currently used frontline artemisinin-based chemotherapy calls for the development of new drugs. Towards this objective and since compounds containing the dibenzazepine moiety are effective in treating both gametocyte and asexual stage malaria parasites, including multi drug resistant parasites, a library of dibenzazepine tethered 3,5-disubstituted isoxazolines was synthesised via 1,3-dipolar cycloaddition reaction. An additional diversified group of dibenzazepine derivatives were accessed by Suzuki coupling of one of the above dibenzazepine derivatives with various organoboronic acids. All compounds were structurally characterized and were evaluated for their antimalarial activity. They exhibited good to excellent inhibitory activity against the growth of drug-sensitive Plasmodium falciparum 3D7 strain with IC50 values ranging from 0.2 to 7.7 μM. About 50{\%} of the compounds were either minimally or not toxic to human cell lines. Five of the compounds (6j, 6k, 8c, 8k and 8l) that highly inhibited the parasite growth were further assessed for antimalarial activity using an additional chloroquine-sensitive (D6) and two chloroquine-resistant (W2 and 7G8) P. falciparum strains. These compounds were effective against all four strains (3D7, D6, W2 and 7G8), exhibiting IC50 values of 0.1 to 1.75 μM. The dibenzazepines were identified to target the metalloamino-peptidase of parasites. Molecular docking and dynamics simulation studies were performed to understand the binding mode and binding strengths of the selected compounds with the enzyme. In agreement with their excellent antimalarial activity, the data suggested that the compounds can strongly bind to the active site of the enzyme.",
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Vinay Kumar, KS, Lingaraju, GS, Bommegowda, YK, Vinayaka, AC, Bhat, P, Pradeepa Kumara, CS, Rangappa, KS, Gowda, DC & Sadashiva, MP 2015, 'Synthesis, antimalarial activity, and target binding of dibenzazepine-tethered isoxazolines', RSC Advances, vol. 5, no. 110, pp. 90408-90421. https://doi.org/10.1039/c5ra17926b

Synthesis, antimalarial activity, and target binding of dibenzazepine-tethered isoxazolines. / Vinay Kumar, Koravangala S.; Lingaraju, Gejjalagere S.; Bommegowda, Yadaganahalli K.; Vinayaka, Ajjampura C.; Bhat, Pritesh; Pradeepa Kumara, Challanayakanahally S.; Rangappa, Kanchugarakoppal S.; Gowda, D. Channe; Sadashiva, Maralinganadoddi P.

In: RSC Advances, Vol. 5, No. 110, 01.01.2015, p. 90408-90421.

Research output: Contribution to journalArticle

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AU - Vinay Kumar, Koravangala S.

AU - Lingaraju, Gejjalagere S.

AU - Bommegowda, Yadaganahalli K.

AU - Vinayaka, Ajjampura C.

AU - Bhat, Pritesh

AU - Pradeepa Kumara, Challanayakanahally S.

AU - Rangappa, Kanchugarakoppal S.

AU - Gowda, D. Channe

AU - Sadashiva, Maralinganadoddi P.

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AB - Malaria, a complex and deadly parasitic infectious disease, is a huge public health problem in many endemic countries around the globe. The prevailing extensive resistance of malaria parasites to traditional drugs and emergence of resistance to the currently used frontline artemisinin-based chemotherapy calls for the development of new drugs. Towards this objective and since compounds containing the dibenzazepine moiety are effective in treating both gametocyte and asexual stage malaria parasites, including multi drug resistant parasites, a library of dibenzazepine tethered 3,5-disubstituted isoxazolines was synthesised via 1,3-dipolar cycloaddition reaction. An additional diversified group of dibenzazepine derivatives were accessed by Suzuki coupling of one of the above dibenzazepine derivatives with various organoboronic acids. All compounds were structurally characterized and were evaluated for their antimalarial activity. They exhibited good to excellent inhibitory activity against the growth of drug-sensitive Plasmodium falciparum 3D7 strain with IC50 values ranging from 0.2 to 7.7 μM. About 50% of the compounds were either minimally or not toxic to human cell lines. Five of the compounds (6j, 6k, 8c, 8k and 8l) that highly inhibited the parasite growth were further assessed for antimalarial activity using an additional chloroquine-sensitive (D6) and two chloroquine-resistant (W2 and 7G8) P. falciparum strains. These compounds were effective against all four strains (3D7, D6, W2 and 7G8), exhibiting IC50 values of 0.1 to 1.75 μM. The dibenzazepines were identified to target the metalloamino-peptidase of parasites. Molecular docking and dynamics simulation studies were performed to understand the binding mode and binding strengths of the selected compounds with the enzyme. In agreement with their excellent antimalarial activity, the data suggested that the compounds can strongly bind to the active site of the enzyme.

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Vinay Kumar KS, Lingaraju GS, Bommegowda YK, Vinayaka AC, Bhat P, Pradeepa Kumara CS et al. Synthesis, antimalarial activity, and target binding of dibenzazepine-tethered isoxazolines. RSC Advances. 2015 Jan 1;5(110):90408-90421. https://doi.org/10.1039/c5ra17926b