Organic Communications

A novel series of amide-based soluble epoxide hydrolase (sEH) inhibitors was rationally designed by incorporating 2,4-dichlorobenzyl and terminal heterocyclic moieties into a central amide scaffold. The target compounds were synthesized and structurally confirmed as new chemical entities using HRMS, 1H NMR, and 13C NMR spectroscopy. Molecular docking studies of the synthesized inhibitors with sEH revealed key hydrogen bonding interactions with Asp335, Tyr383, and Tyr466, along with π–π stacking interactions with His524 and Trp525, indicating their effective binding to the sEH active site.  In vitro biological evaluation showed that all synthesized derivatives exhibit potent sEH inhibitory activity at both 10 and 100 nM, with compound 11 emerging as the most promising lead for further development of potent anti-inflammatory agents.

We have thoroughly investigated the C-benzylation of pyrrole (1) using different second and third generation ionic liquids (ILs). The pyrrole C-benzylation is achieved with benzyl halides, mesylate, and tosylate selectively at C2 position in good yield. Moreover, minimal byproducts under relatively mild conditions in hexaethylene glycol substituted imidazolium based ILs (hexaEGILs) have been observed. 2-Benzyl pyrrole (3) was synthesized in high yield from pyrrole (1) and benzyl bromide (2a) in the presence of [hexaEGmim][OMs] and [dihexaEGim][OMs] as two different tailor-made ILs as catalysts (10 mol%) in MeCN at 80 oC within an hour.

A series of nitrile derivatives of Petromurin C were synthesized and assessed for their cytotoxic effects on tumor cell lines and inhibitory activity against Mycobacterium tuberculosis (M.tb H37Ra). Bromoalkyl nitriles (Br(CH2)nCN; n=1-5) and (o-, m-, p-) bromomethyl benzonitriles were used as alkylating reagents. The majority of the syntheses consisted of O-alkylated derivatives in which the two NH group were not alkylated, as expected from the treatment of petromurin C with K2CO3 in DMF followed by treatment with alkylating reagents. Similarly, treatment of Petromurin C with NaH in DMF and the treatment with alkylating reagents yielded both OR and bis-NR alkylated structures. In the first method, 7 different O-alkyl Petromurin C derivatives were obtained.  The second method yielded 7 different Petromurin-C derivatives containing both O-alkyl and bis-N-alkyl groups. Notably, compounds 1-4 and 7-10 demonstrated selective inhibitory activity against the acute myeloid leukemia cell line MV4-11, with IC50 values ranging from 12.96 to 20.00 μM. Compound 15 exhibited a minimum inhibitory concentration (MIC) of 6.25 μM against M.tb H37Ra. Importantly, all synthesized compounds showed negligible inhibition (below 50%) against human normal cell lines L-02 and 293T at a concentration of 100 μM. These findings suggest that the compounds possess high efficacy and low toxicity, indicating their potential as novel therapeutic agents for the treatment of leukemia and tuberculosis. 

Cyclohexanecarboxamido hydrazones constitute a promising new class of therapeutic candidates exhibiting notable antioxidant, antibacterial, anticancer, and anti-inflammatory activities. In contrast to conventional hydrazones, these compounds combine the versatile hydrazone pharmacophore with a drug-like cyclohexyl amide moiety, a structural feature that may improve bioavailability, metabolic stability, and overall therapeutic performance. This study shows that, a series of sixteen novel derivatives. 2-(1-(4-chlorophenyl)cyclohexane-carboxamido)-N′-arylidenoacetohydrazides (8a–8p), were synthesized through a six-step pathway starting from 2-(4-chlorophenyl)acetic acid. The key hydrazide intermediate was condensed with various substituted aromatic aldehydes, affording the target hydrazones in good to excellent yields (72–86%). Structures of all compounds were confirmed by 1H NMR, 13C NMR, IR, LC-MS, and elemental analysis. The synthetic methodology demonstrated broad functional group tolerance, thus providing a reliable platform for generating structurally diverse analogues in consistently high yields.