Targeting malaria and leishmaniasis: Synthesis and pharmacological evaluation of novel pyrazole-1,3,4-oxadiazole hybrids. Part II.

In continuance with earlier reported work, an extension has been carried out by the same research group. Mulling over the ongoing condition of resistance to existing antimalarial agents, we had reported synthesis and antimalarial activity of certain pyrazole-1,3,4-oxadiazole hybrid compounds. Bearing previous results in mind, our research group ideated to design and synthesize some more derivatives with varied substitutions of acetophenone and hydrazide. Following this, derivatives 5a-r were synthesized and tested for antimalarial efficacy by schizont maturation inhibition assay. Further, depending on the literature support and results of our previous series, certain potent compounds (5f, 5n and 5r) were subjected to Falcipain-2 inhibitory assay. Results obtained for these particular compounds further strengthened our hypothesis. Here, in this series, compound 5f having unsubstituted acetophenone part and a furan moiety linked to oxadiazole ring emerged as the most potent compound and results were found to be comparable to that of the most potent compound (indole bearing) of previous series. Additionally, depending on the available literature, compounds (5a-r) were tested for their antileishmanial potential. Compounds 5a, 5c and 5r demonstrated dose-dependent killing of the promastigotes. Their IC50 values were found to be 33.3 ±â€¯1.68, 40.1 ±â€¯1.0 and 19.0 ±â€¯1.47 µg/mL respectively. These compounds (5a, 5c and 5r) also had effects on amastigote infectivity with IC50 of 44.2 ±â€¯2.72, 66.8 ±â€¯2.05 and 73.1 ±â€¯1.69 µg/mL respectively. Further target validation was done using molecular docking studies. Acute oral toxicity studies for most active compounds were also performed.

Unveiling novel diphenyl-1H-pyrazole based acrylates tethered to 1,2,3-triazole as promising apoptosis inducing cytotoxic and anti-inflammatory agents.

Meagre and suboptimal therapeutic response along with the side effect profile associated with the existing anticancer therapy have necessitated the development of new therapeutic modalities to curb this disease. Bearing in mind the current scenario, a series of 1,2,3-triazole linked 3-(1,3-diphenyl-1H-pyrazol-4-yl)acrylates was synthesized following a multi-step reaction scheme. Initial screening for anticancer potential was done by in vitro sulforhodamine B assay against four human cancer cell lines- MCF-7 (breast), A549 (Lung) and HCT-116 and HT-29 (Colon). On evaluation, several compounds showed promising growth inhibition against all the cell lines, particularly compounds 6e, 6f and 6n. Among them, compound 6f displayed IC50 values of 1.962, 3.597, 1.764 and 4.496 µM against A549, HCT-116, MCF-7 and HT-29 cell lines respectively. Furthermore, the apoptosis inducing potential of the compounds was determined by Hoechst staining and DNA fragmentation assay. Colony formation inhibition assay was also carried out to determine the long term cytotoxic potential of the molecules. Moreover, compounds 6e, 6f and 6n were also evaluated for anti-inflammatory activity by protein albumin denaturation assay and red blood cell membrane stabilizing assay.

Synthesis and antimicrobial activity of some novel oxadiazole derivatives.

A series of 5-(3'-oxo-6'-(substituted aryl)-2',3',4',5'-tetrahydropyridazin-2'-ylmethyl )-2-substituted 1,3,4-oxadiazole has been synthesized. Appropriate aromatic hydrocarbon reacts with succinic anhydride in the presence of AICl3 to yield beta-aroyl propionic acid (1a). The corresponding acid is cyclized with hydrazine hydrate to give 6-(substituted aryl)-2,3,4,5-tetrahydro-3-pyridazinone (1b). This ntermediate after reaction with ethyl bromoacetate, was hydrazinolyzed into 3-oxo-6-(substituted aryl)-2, 3, 4, 5-tetrahydropyridazinyl acetohydrazide (1c). The resulting product was converted into 5-[3'-oxo-6'-(substituted aryl)-2',3',4',5'-tetrahydropyridazin-2'-ylmethyl]-2-substituted 1,3,4-oxadiazole (Scheme 1). All the final compounds were structurally elucidated on the basis of IR, H-NMR, MS data and elemental analysis and screened for antibacterial, antifungal and antitubercular activity. All the compounds are evaluated for their antibacterial activity against E. coli, S. aureus, Micrococcus luteus and Klebsiella pneumoniae by using cup plate technique in the nutrient agar at 100 microg/mL concentration. Antitubercular activity was determined using the BACTEC 460 system. Stock solutions of test compounds were prepared in DMSO. MIC of rifampin was calculated by established procedures. All the synthesized compounds were screened at 6.25 microg/mL against M. tuberculosis H37 Rv comparable with that of standard rifampicin and isoniazid. All the final compounds were evaluated for antifungal activity against C. albicans and C. neoformans by using cup-plate method in the Sabouraud agar media The zone of inhibition (mm) of each compound was determined and compared with standard drug fluconazole.