Abstract
Leishmaniasis is one of the major parasitic diseases, caused by obligate intracellular protozoa Leishmania, having high mortality as well as morbidity rate. As there is no human licensed vaccine available against leishmaniasis, chemotherapy remains the major way of combating this disease. Many disadvantages are known to be associated with the current drug regime including severe side effects and toxicity, long duration and expensive treatment, and the emergence of resistance. An alternative approach is being utilized to search for active molecules using natural sources, rather than relying on synthetic drugs. Many plant-derived secondary metabolites like phenolic compounds, steroids, quinones, etc. are being extensively investigated for their anti-leishmanial potential. One such group of complex phenolic compounds are diarylheptanoids. These compounds have been shown to exhibit anti-inflammatory, anti-parasitic, anti-fungal, and other pharmacological activities. In the present study, a set of sixteen tetrahydropyran derivatives including three natural products were obtained in lyophilized form. These compounds with trans-2,6-disubstituted tetrahydropyrans, Diospongin A, Diospongin B (isolated from Dioscorea spongiosa) and Centrolobine (Centrolobium sclerophyllum) as parent compounds were synthesized by the reaction of 1-phenyl-1-triemthylsiloxyethylene with six-membered cyclic hemiacetals in the presence of iodine as a catalyst. All the sixteen synthesized tetrahydropyran derivatives were used for toxicity analysis against L. donovani promastigotes, amastigotes and THP-1-derived human macrophages. IC50 values and selectivity index were calculated for all the compounds. Out of these sixteen, five compounds showed the best effect in vitro in terms of both leishmanicidal activity and non-toxicity to human macrophages.
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Abbreviations
- CL:
-
Cutaneous leishmaniasis
- VL:
-
Visceral leishmaniasis
- MCL:
-
Mucocutaneous leishmaniasis
- PKDL:
-
Post kala-azar dermal leishmaniasis
- L. donovani :
-
Leishmania donovani
- L. major :
-
Leishmania major
- L. amazonensis :
-
Leishmania amazonensis
- THP-1:
-
Tohuku Hospital Pediatrics-1
- DMSO:
-
Dimethylsulfoxide
- FBS:
-
Fetal Bovine Serum
- MTT:
-
3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- SDS:
-
Sodium Dodecyl Sulphate
- PMA:
-
Phorbol-12-myristate-13-acetate
- IC50 :
-
Inhibitory concentration 50%
- WHO:
-
World Health Organization
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Acknowledgements
We thank the Central Instrumentation Facility at the School of Life Sciences, Jawaharlal Nehru University, for providing the imaging facility.
Funding
Rentala Madhubala is an AS Paintal Distinguished Scientist Chair of ICMR. Smriti Tandon is a recipient of funding from the Indian Council of Medical Research, India. Madhu Puri is a recipient of the University Grants Commission- D.S. Kothari Post-Doctoral Fellowship.
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ST: Methodology (Screening of inhibitors for antileishmanial activity), Writing—original draft, writing—review and editing. MP: Methodology (Screening of inhibitors for antileishmanial activity), writing—review and editing. YB: Methodology (synthesis of the sixteen compounds), writing—review and editing. UMC: Methodology (synthesis of the sixteen compounds), writing—review and editing. DKM: Supervision, methodology (synthesis of the sixteen compounds) writing—review and editing, RM: Supervision, writing—review and editing. RM: Conceptualization, supervision, funding acquisition, writing- original draft, writing—review and editing.
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Tandon, S., Puri, M., Bharath, Y. et al. In vitro screening of natural product-based compounds for leishmanicidal activity. J Parasit Dis 47, 644–658 (2023). https://doi.org/10.1007/s12639-023-01605-7
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DOI: https://doi.org/10.1007/s12639-023-01605-7