Pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs as possible candidates against neglected tropical diseases (NTDs): identification of hit compounds towards development of potential treatment of Leishmania donovani

Abstract

A rational-based process was adopted for repurposing pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs bearing variable acyl chains, different stereochemical configuration and/or positional relationships. Structural features were highly influential on activity. Amongst, enantiomer 1e having 1,2-vicinal relationship for the -CH 2 O- and the N- acyl moieties, a saturated palmitoyl chain and an opposite stereochemical configuration to natural sphingolipids was the most potent hit compound against promastigotes showing IC 50 value of 28.32 µM. The corresponding enantiomer 1a was 2-fold less potent showing a eudismic ratio of 0.54 in promastigotes. Compounds 1a and 1e inhibited the growth of amastigotes more potently relative to promastigotes. Amongst, enantiomer 1a as the more selective and safer. In silico docking study using a homology model of Leishmania donovani inositol phosphoceramide synthase (IPCS) provided plausible reasoning for the molecular factors underlying the found activity. Collectively, this study suggests compounds 1a and 1e as potential hit compounds for further development of new antileishmanial agents.

In Silico and In Vitro Evaluation of Some Amidine Derivatives as Hit Compounds towards Development of Inhibitors against Coronavirus Diseases

“…Hit discovery and confirmation is an indispensable first step in early drug discovery [ 34 , 35 , 36 , 37 , 38 ]. While a hit compound would show the desired type of activity, its activity might be of low potential and/or it can possess undesirable effects.…”

Identification of SARS‐CoV‐2 Papain‐like Protease (PLpro) Inhibitors Using Combined Computational Approach**

“…The continuous increase of drug-resistant pathogens is a challenge for the treatment of infectious diseases, and drug repurposing represents an alternative approach for the fast identification of effective therapeutics. [25] Computational drug repurposing was an essential step in successfully affording agents against other pathogenic diseases, [26] inflammation, [27] cancer. [28] The fundamental problem in a search for preventive and therapeutic options to respond to threats of a pandemic is a costly, time-consuming, and risky process of drug development.…”

“…The continuous increase of drug‐resistant pathogens is a challenge for the treatment of infectious diseases, and drug repurposing represents an alternative approach for the fast identification of effective therapeutics [25] . Computational drug repurposing was an essential step in successfully affording agents against other pathogenic diseases, [26] inflammation, [27] cancer [28]…”

Isolation of Sesquiterpenoids and Steroids from the Soft Coral Sinularia brassica and Determination of Their Absolute Configuration

“…Antileishmanial activity was evaluated according to the protocol of Institut Pasteur Korea [ 22 ]. Antimicrobial activity was determined by dropping compounds on agar plate covered with S. aureus KCTC 3881 (bacterium), E. coli DH5α (bacterium) and C. albicans KCTC 27242 (fungus) (Korean Collection for Type Cultures, Daejeon, Korea).…”