Synthesis, in-vitro antiprotozoal activity and molecular docking study of isothiocyanate derivatives.

Novel isothiocyanate derivatives were synthesized starting from noscapine, bile acids, amino acids, and some aromatic compounds. Antiparasitic activities of the synthesized derivatives were tested against four unicellular protozoa, i.e., Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani, and Plasmodium falciparum. Interestingly, seven isothiocyanate analogues displayed promising antiparasitic activity against Leishmania donovani with IC50 values between 0.4 and 1.0 µM and selectivity index (SI) ranged from 7.8 to 18.4, comparable to the standard drug miltefosine (IC50 = 0.7 µM). Compound 7h demonstrated the best antileishmanial activity with an IC50 value of 0.4 µM. Seven products exhibited inhibition activity against T. brucei rhodesiense with IC50s below 2.0 µM and SI between 2.7 and 29.3. Four primary amine derivatives of noscapine and five isothiocyanate derivatives exhibited antiplasmodial activity with IC50s in the range of 1.1-2.7 µM and SI values between 1.1 and 14.5. The isothiocyanate derivative 7c showed against T. cruzi with an IC50 value of 1.9 µM and SI 4. Molecular docking and ADMET studies were performed to investigate the interaction between active ligands and T. brucei trypanothione reductase active site. The docking studies showed significant binding affinity of noscapine derivatives to enzyme active site and good compatibility with experimental data.

N-substituted noscapine derivatives as new antiprotozoal agents: Synthesis, antiparasitic activity and molecular docking study.

Novel N-substituted noscapine derivatives were synthesized by a three-component Strecker reaction of cyclic ether of N-nornoscapine with varied aldehydes, in the presence of cyanide ion. Moreover, the corresponding amides were synthesized by the oxidation of cyanide moieties in good yields. The in vitro antiprotozoal activity of the products was also investigated. Interestingly, some analogues did put on display promising antiparasitic activity against Trypanosoma brucei rhodesiense with IC50 values between 2.5 and 10.0 µM and selectivity index (SI) ranged from 0.8 to 13.2. Eight compounds exhibited activity against Plasmodium falciparum K1 strain with IC50 ranging 1.7-6.4 µM, and SI values between 2.8 and 10.5 against L6 rat myoblast cell lines. Molecular docking was carried out on trypanothione reductase (TbTR, PDB ID: 2WOW) and UDP-galactose 4' epimerase (TbUDPGE PDB: 1GY8) as targets for studying the envisaged mechanism of action. Compounds 6j2 and 6b2 displayed excellent docking scores with -8.59 and -8.86 kcal/mol for TbTR and TbUDPGE, respectively.