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An insight into tetrahydro-?-carboline-tetrazole hybrids: synthesis and bioevaluation as potent antileishmanial agents.

ABSTRACT: A series of 2,3,4,9-tetrahydro-?-carboline tetrazole derivatives (14a-u) have been synthesized utilizing the Ugi multicomponent reaction and were identified as potential antileishmanial chemotypes. Most of the screened derivatives exhibited significant in vitro activity against the promastigote (IC₅₀ from 0.59 ± 0.35 to 31 ± 1.27 ?M) and intracellular amastigote forms (IC₅₀ from 1.57 ± 0.12 to 17.6 ± 0.2 ?M) of L. donovani, and their activity is comparable with standard drugs miltefosine and sodium stibogluconate. The most active compound 14t was further studied in vivo against the L. donovani/golden hamster model at a dose of 50 mg kg^-1 through the intraperitoneal route for 5 consecutive days, which displayed 75.04 ± 7.28% inhibition of splenic parasite burden. Pharmacokinetics of compound 14t was studied in the golden Syrian hamster, and following a 50 mg kg^-1 oral dose, the compound was detected in hamster serum for up to 24 h. It exhibited a large volume of distribution (651.8 L kg^-1), high clearance (43.2 L h^-1 kg^-1) and long mean residence time (10 h).

SUBMITTER: Purohit P

PROVIDER: S-EPMC6084189 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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An insight into tetrahydro-β-carboline-tetrazole hybrids: synthesis and bioevaluation as potent antileishmanial agents.

Purohit Pooja P Pandey Anand Kumar AK Singh Deepti D Chouhan Pradeep Singh PS Ramalingam Karthik K Shukla Mahendra M Goyal Neena N Lal Jawahar J Chauhan Prem M S PMS

MedChemComm 20170721 9

A series of 2,3,4,9-tetrahydro-β-carboline tetrazole derivatives (14a-u) have been synthesized utilizing the Ugi multicomponent reaction and were identified as potential antileishmanial chemotypes. Most of the screened derivatives exhibited significant in vitro activity against the promastigote (IC50 from 0.59 ± 0.35 to 31 ± 1.27 μM) and intracellular amastigote forms (IC50 from 1.57 ± 0.12 to 17.6 ± 0.2 μM) of L. donovani, and their activity is compara ...[more]

PMID: 30108893

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Project description:Background and purposeAlthough pain is one of the most common symptoms of diseases, it is often mismanaged due to limited access to painkillers and ineffectiveness, unacceptable side effects, or the possibility of abuse. However, an alternative approach to existing analgesics is to indirectly increase endogenous pain relief pathways by neprilysin (an enkephalinase) inhibitors. This enzyme breaks down and inactivates enkephalin, dynorphin, endorphins, and their derivatives.Experimental approachIn this project, a new series of racecadotril-tetrazole-amino acid derivatives 15a-l was synthesized and characterized on the basis of IR, 1H and 13C NMR, mass spectrometry, and elemental analysis. The antinociceptive activity of synthesized compounds was assessed by a hot plate, tail-flick, and formalin assays in mice. Docking was used to identify the possible interactions between neprilysin and synthesized compounds. 15a-l was synthesized and characterized on the basis of IR, 1H and 13C NMR, mass spectrometry, and elemental analysis. The antinociceptive activity of synthesized compounds was assessed by a hot plate, tail-flick, and formalin assays in mice. Docking was used to identify the possible interactions between neprilysin and synthesized compounds.Findings/resultsMost of the synthesized compounds showed moderate to good analgesic effects in hot plat and tail-flick test in comparison to morphine and racecadotril. Compounds 15l and 15j were the most potent compounds. The synergistic analgesic effect of compounds 15l and 15j with morphine and the antagonistic effect of naloxone on the activity of these compounds confirm that the analgesic effect of compounds 15l and 15j could be mediated through the opioidergic system. The negative and high binding energy of docking simulation of the most potent compounds in the catalytic site of neprilysin was also in good agreement with the inhibitory activity of test compounds.Conclusion and implicationsRacecadotril-tetrazole-amino acid derivatives, as potential antinociceptive agents, demonstrated moderate to good antinociceptive activities comparable with morphine and higher than racecadotril.

Dataset Information

An insight into tetrahydro-?-carboline-tetrazole hybrids: synthesis and bioevaluation as potent antileishmanial agents.

Publications

An insight into tetrahydro-β-carboline-tetrazole hybrids: synthesis and bioevaluation as potent antileishmanial agents.

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