A Versatile Pre and Post Ugi Modification for the Synthesis of Natural Product Inspired Fused Peptide‐Carboline Scaffolds as Potential Anti‐Leishmanial Agents

Abstract

A series of novel β‐carboline‐peptide (5 a‐5 f)/ tetrahydro‐β‐carbolines‐peptide (10 a‐10 f) has been synthesized via natural product inspired molecular hybridization approach. All the hybrids were examined for their anti‐leishmanial potential. Most of the screened derivatives exhibited significant in vitro anti‐leishmanial activity against promastigote and intracellular amastigotes (IC50 ranging from 2.43 to 7.61 μM) than the control, miltefosine (IC50 = 8.2 μM), with less cytotoxicity in comparison to the standard drugs (sodium stibogluconate, and miltefosine). Compound 5 a was also able to inhibit Leishmania donovani TR (LdTR). A molecular modeling study based on docking and subsequent binding free energy evaluation was carry out in the active site of LdTR to understand their possible binding site. Our results show that prototype 1(5 a‐5 f) & 2 (10 a‐10 f) represent a new structural lead for anti‐leishmanial Chemotherapy.

Recent evolution on synthesis strategies and anti-leishmanial activity of β-carboline derivatives – An update

“…Among the tested compounds, compounds 148, 149, and 1 50 revealed significant in-vitro anti-leishmanial activity against both promastigotes and intracellular amastigotes of L. donovani (IC 50 2.43, 3.56, and 7.61 μM, respectively) than the control drug miltefosine (IC 50 = 8.2 μM)with less cytotoxicity when compared with the standard drugs (sodium stibogluconate and Miltefosine). In-silico molecular docking studies of the synthesized compounds using the homology modeled LdTR indicated that the compound 149 showed significant binding free energy when compared with compound 1 50 ( Khan et al., 2019 ) (see Figure 18 ) .

Figure 18 Structure of compounds 148, 149 and 150 .

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Recent developments in the total synthesis of natural products using the Ugi multicomponent reactions as the key strategy

“…Furthermore, coupled with other synthetic strategies, the Ugi-type reactions have also been employed for the preparation of natural product hybrids by diversification; these include terpenes, steroids, 36 alkaloids, and other metabolites, 37 and the synthesis of natural product-like compounds, particularly nitrogen heterocycles. 38 Finally, peptidomimetics integrating heterocyclic, lipidic, and sugar moieties have also been easily assembled.…”