New indenopyrazole linked oxadiazole conjugates as anti-pancreatic cancer agents: Design, synthesis, in silico studies including 3D-QSAR analysis.

To continue the quest of newer anticancer agents, herein a novel class of 1,4-Dihydroindenopyrazole linked oxadiazole conjugates 9(a-r) was designed, synthesized and experimented for their anti-proliferative activities against four different cancer cell lines (human) such as MDA MB-231 (breast), PANC-1 (pancreatic), MCF-7 (breast), and Caco-2 (Colorectal) by using MTT assay. Among the series compound 9h and 9 m demonstrated significant potency against the PANC-1 (human pancreatic cancer cells) with IC50 value 7.4 µM and 4.3 µM respectively. While compound 9 m was found to be equipotent to standard Gomitabine (IC50 = 4.2 µM). The detailed biological assays revealed S phase cell cycle arrest and their ability to propagate apoptosis by activating caspase 3 and 9 enzymes which was confirmed by Annexin-FITC assay and caspase assay. Moreover, docking study suggested their binding modes and interactions with caspase-3. In addition, in silico studies revealed that they exhibit good pharmacokinetics and drug likeliness properties. Furthermore, 3D-QSAR was carried out to achieve a pharmacophoric model with CoMFA (q2 = 0.631, r2 = 0.977) and CoMSIA (q2 = 0.686, r2 = 0.954) on PANC-1 cancer cells which were established, generated and validated to be reliable models for further design and optimization of newer molecules with enhanced anticancer activity.

Synthesis of new triazole fused imidazo[2,1-b]thiazole hybrids with emphasis on Staphylococcus aureus virulence factors.

A series of new triazole fused imidazo[2,1-b]thiazole hybrids (9a-u) were designed, synthesized and evaluated as antimicrobial agents. Compounds 9c, 9d, 9e, 9j and 9l showed promising broad spectrum antimicrobial activity. Further, compound 9c exhibited significant anti-biofilm activity with single and mixed biofilm disruption demonstrated by Field Emission Scanning Electron Microscope (FE-SEM). Furthermore, molecular docking studies revealed that they interact with the virulence factor, Staphylococcus aureus dehydrosqualene synthase (CrtM) (PDB ID: 2ZCS). Overall, the findings suggest compound 9c as potential lead for further development of novel antibacterial and anti-biofilm agents.

Synthesis of new bis-pyrazole linked hydrazides and their in vitro evaluation as antimicrobial and anti-biofilm agents: A mechanistic role on ergosterol biosynthesis inhibition in Candida albicans.

Literature reports suggest that pyrazoles and hydrazides are potential antimicrobial pharmocophores. Considering this fact, a series of nineteen conjugates containing hybrids of bis-pyrazole scaffolds joined through a hydrazide linker were synthesized and further evaluated for their antimicrobial activity against a panel of Gram-positive and Gram-negative bacteria along with Candida albicansMTCC 3017 strain. Although the derivatives exhibited good antibacterial activity, some of the derivatives (13d, 13j, 13l, 13p, and 13r) showed excellent anti-Candida activity with MICs values of 3.9 µg/ml, which was equipotent to that of the standard Miconazole (3.9 µg/ml), which has inspired us to further explore their anti-Candida activity. The same compounds were also tested for anti-biofilm studies against various Candida strains and among them, compounds 13l and 13r efficiently inhibited the formation of fungal biofilms. Field emission scanning electron micrographs revealed that one of the promising compound 13r showed cell damage and in turn cell death of the Candida strain. These potential conjugates (13l and 13r) also demonstrated promising ergosterol biosynthesis inhibition against some of the strains C. albicans, which were further validated through molecular docking studies. In silico computational studies were carried out to predict the binding modes and pharmacokinetic parameters of these conjugates.