Sulfur (Sâ ¥)-containing heterocyclic hybrids as antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA) and its SAR.

The discovery of new small molecule-based inhibitors is an attractive field in medicinal chemistry. Structurally diversified heterocyclic derivatives have been investigated to combat multi-drug resistant bacterial infections and they offers several mechanism of action. Methicillin-resistant Staphylococcus aureus (MRSA) is becoming more and more deadly to humans because of its simple method of transmission, quick development of antibiotic resistance, and ability to cause hard-to-treat skin and filmy diseases. The sulfur (SVI) particularly sulfonyl and sulfonamide based heterocyclic moieties, have found to be good anti-MRSA agents. The development of new nontoxic, economical and highly active sulfur (SVI) containing derivatives has become hot research topics in drug discovery research. Presently, more than 150 FDA approved Sulfur (SVI)-based drugs are available in the market, and they are widely used to treat various types of diseases with different therapeutic potential. The present collective data provides the latest advancements in Sulfur (SVI)-hybrid compounds as antibacterial agents against MRSA. It also examines the outcomes of in-vitro and in-vivo investigations, exploring potential mechanisms of action and offering alternative perspectives on the structure-activity relationship (SAR). Sulfur (SVI)-hybrids exhibits synergistic effects with existing drugs to provide antibacterial action against MRSA.

Synthesis of p-CuO/n-ZnO heterostructure by microwave hydrothermal method and evaluation of its photo and bio-catalytic performance.

The use of photocatalysts without noble metals is of great interest in the industrial field for the degradation of organic pollutants. In this study, a CuO/ZnO heterostructure was synthesized using the microwave hydrothermal method and characterized using various analytical techniques. The synthesized CuO/ZnO photocatalyst exhibited a low bandgap energy of 2.4 eV, enabling efficient visible light absorption. The photocatalytic activity of the CuO/ZnO heterostructure was evaluated for the degradation of Methyl Orange (MO) dye and showed a high degradation efficiency of 99 % due to its excellent electron-hole charge separation. The biological activity of the synthesized CuO/ZnO catalyst was further investigated through protein docking studies, which showed promising results. The CuO/ZnO was also evaluated for its anticancer and antibacterial properties. It exhibited effective anticancer activity against prostate cancer cells (PC-3) in a dose-dependent manner, with an IC50 value of 6.87 ± 8. In addition, it demonstrated potent antibacterial activity against Escherichia coli, Staphylococcus aureus, Bacillus cereous and Pseudomonas aeruginola. The results of this study demonstrate the potential of CuO/ZnO heterostructures as promising materials for various applications in the fields of photocatalysis, biomedicine and antimicrobial materials. Future research in this area will focus on further optimizing the properties of the CuO/ZnO heterostructure to enhance its performance in these applications.

Alternative Approach to Access 5-Hydroxy-1H-pyrrol-2-(5H)-ones from Base-Induced Tandem Intramolecular Cyclization of Sulfur Ylide with Ketones and 1,3-Hydroxy Rearrangement.

An easily adaptable protocol for the preparation of 5-hydroxy-1H-pyrrol-2(5H)-ones from readily available starting materials has been reported. The reaction of sulfur ylides with carbonyl compounds is a common approach to synthesizing epoxides. Alternatively, we have developed a method with mild reaction conditions wherein sulfur ylide underwent an intramolecular cyclization with a ketonic carbonyl group in a highly efficient way and was followed by 1,3-hydroxy rearrangement to produce 5-hydroxy-1H-pyrrol-2(5H)-ones in excellent yields. The present method offers a straightforward approach to synthesize 5-hydroxy-1H-pyrrol-2(5H)-ones from sulfur ylides without the aid of transition metal in one-pot operation, which involves sequential cyclization and rearrangement reaction. The formation of 5-hydroxy-1H-pyrrol-2(5H)-ones is supported by different spectroscopic techniques, including X-ray crystallographic data and 2D NMR studies (COSY, HSQC, HMBC, and DEPT).

Design and synthesis of 4-aminophenol-1,3,4-oxadiazole derivative potentiates apoptosis by targeting MAP kinase in triple negative breast cancer cells.

Women below 40 years greatly suffer from triple negative breast cancers (TNBCs). Compared to other breast cancer cases, the poor prognosis and lower survival rate of TNBC patients make it an alarming task to save the human era from this dreadful disease. Therefore, identifying potential novel leads is urgently required to combat the TNBC. To discover a novel anticancer agent, we synthesized a series of novel 4-aminophenolbenzamide-1,3,4 oxadiazole hybrid analogues (7a-l). The structure of the compounds was confirmed by spectral methods (1H & 13C NMR, IR and MS). All the compounds were subjected to their in-silico and in-vitro antiproliferative studies against the TNBC cell lines MDA-MB-468 and MDA-MB-231. The investigations revealed that 7i has significantly promoted apoptosis against MDA-MB-468 and MDA-MB-231 cells with IC50 values of 16.89 and 19.43 µM, respectively. Molecular docking of 7i, with MAPK has exhibited the highest binding score of -7.10 kcal/mol by interacting with crucial amino acids present at the active sites. Molecular docking is further validated with molecular dynamic studies with simulation for 100 ns, depicting various stable interactions with MAPK. Compound 7i, forms stable H-bonds and π-π stacking with amino acid residues. Molecular dynamic simulation (MDS) reveals that hydrophobic and water bridges were very prominent for 7i to bind, with the amino acid residues in close proximity to the active site of p38 MAPK. The investigations show that the In-vitro antiproliferative study of 7i agreed with the in-silico studies. Collectively, our investigations depict 7i as a potent novel lead for the inhibition of TNBCs by targeting p38 MAPK.Communicated by Ramaswamy H. Sarma.

A novel 4-aminophenolbenzamide-1,3,4 oxadiazole library of small molecules displayed potent antiproliferative activity.Compound 7i induces apoptosis significantly against triple-negative breast cancer cells.Compound 7i potentiates apoptosis by targeting p38 MAPK and altering mitochondrial membrane potential.Molecular docking and molecular dynamic simulation (MDSs) confirm the efficient binding of compound 7i with MAPK (Docking score of −7.10 kcal/mol).

Microwave assisted one-pot access to pyrazolo quinolinone and tetrahydroisoxazolo quinolinone derivatives via T3P®-DMSO catalysed tandem oxidative-condensation reaction.

A new approach for the synthesis of two important annulated pyrazolo quinolinone and tetrahydroisoxazolo quinolinone derivatives from multicomponent reactions was achieved by using T3P®-DMSO-catalysed reactions of stable alcohols, cyclic 1,3-dicarbonyl compounds and amino derivatives of phenyl pyrazoles and isoxazole and has been reported for the first time. This reaction occurred via a tandem oxidative-condensation reaction under microwave irradiation and notable characteristics of this protocol are MCR reactions, shorter reaction time, less waste creation, ease of workup, stable precursors, broad substrate scope and functional group tolerance.

Design, synthesis and docking studies of novel 4-aminophenol-1,2,4-oxadiazole hybrids as apoptosis inducers against triple negative breast cancer cells targeting MAP kinase.

In our study, a series of novel 4-aminophenol benzamide-1,2,4-oxadiazole hybrid analogues have been designed and synthesized by condensing 4-hydroxyphenyl arylamides (3a-c) and 5-chloromethyl-3-aryl-1,2,4-oxadiazoles (6a-d). The structure of the synthesised compounds was verified by various spectroscopic techniques (1H NMR, 13C NMR, IR and LC-MS). All the prepared compounds were subjected to in silico and in vitro antiproliferative study against TNBC cell lines MDA-MB-468 and MDA-MB-231. The investigations revealed that compound 7k significantly promoted apoptosis against MDA-MB-468 and MDA-MB-231 cells with IC50 values of 22.31 µM and 26.27 µM, respectively. Compound 7k interacted with crucial active sites of MAPK and exhibited the highest docking score of -7.06 kcal/mol. Docking was validated with molecular dynamic studies with simulation for 100 ns, depicting various stable interactions with MAPK. Consequently, 7k forms stable H-Bonds and π-π stacking with amino acid residues along with π-cation. Our investigations reveal that the in vitro antiproliferative study of 7k was in good correlation with the in silico studies. Hence, 7k serves as a potential novel lead for the inhibition of TNBCs by downregulating MAPK P38.Communicated by Ramaswamy H. Sarma.

Novel 4-aminophenol benzamide-1,2,4 oxadiazole library of small molecules displayed potent antiproliferative activity.Compound 7k induces apoptosis significantly against triple-negative breast cancer cells.Compound 7k potentiates apoptosis by targeting MAPK P38 and altering mitochondrial membrane potential.Molecular docking and molecular dynamic simulations confirm the efficient binding of compound 7k with MAPK (Docking score of ­7.06 kcal/mol).

Noncoding RNAs as regulators of STAT3 pathway in gastrointestinal cancers: Roles in cancer progression and therapeutic response.

Gastrointestinal (GI) tumors (cancers of the esophagus, gastric, liver, pancreas, colon, and rectum) contribute to a large number of deaths worldwide. STAT3 is an oncogenic transcription factor that promotes the transcription of genes associated with proliferation, antiapoptosis, survival, and metastasis. STAT3 is overactivated in many human malignancies including GI tumors which accelerates tumor progression, metastasis, and drug resistance. Research in recent years demonstrated that noncoding RNAs (ncRNAs) play a major role in the regulation of many signaling pathways including the STAT3 pathway. The major types of endogenous ncRNAs that are being extensively studied in oncology are microRNAs, long noncoding RNAs, and circular RNAs. These ncRNAs can either be tumor-promoters or tumor-suppressors and each one of them imparts their activity via different mechanisms. The STAT3 pathway is also tightly modulated by ncRNAs. In this article, we have elaborated on the tumor-promoting role of STAT3 signaling in GI tumors. Subsequently, we have comprehensively discussed the oncogenic as well as tumor suppressor functions and mechanism of action of ncRNAs that are known to modulate STAT3 signaling in GI cancers.

Coumarin derivative as a potent drug candidate against triple negative breast cancer targeting the frizzled receptor of wingless-related integration site signaling pathway.

Triple negative breast cancer constitutes to about 21.8 percent of the total breast cancer related cases. Its ability to affect young ladies and in pre-menstrual stage makes this a disease of concern worldwide. The current treatment regimens involve chemotherapy which are used for treatment of other cancer types. In this regard, there is a need for specific and targeted drug candidate for its effective treatment. In the current study, assessment of coumarin derivative 2-(2-(6- Methyl-2-Oxo-2H-chromen-4-yl) acetamido)-3-phenylpropanoic acid is carried out both In-silico and In-vitro methods. Frizzled transmembrane proteins of Wingless-related integration site signaling pathway was targeted in which Frizzled-7 proved to a prospective target and showed a binding energy of -6.78 kcal/mol. The complex was subjected to molecular dynamics simulation for 200 ns and showed stable interaction with cysteine rich domain of the receptor. Cell proliferation, viability and apoptosis assay were performed on MDA-MB-231 and MDA-MB-468 cell lines with an IC50 value of 81.23 and 84.68 µM, respectively. The results provide a drug candidate which is derivative of a natural compound with targeted TNBC inhibitory effect. Communicated by Ramaswamy H. Sarma.

Brucein D imparts a growth inhibitory effect in multiple myeloma cells by abrogating the Akt-driven signaling pathway.

The Akt signaling pathway is an oncogenic cascade activated in the bone marrow microenvironment of multiple myeloma (MM) cells and contributes to their uncontrolled proliferation. Abrogation of Akt signaling has been presented as one of the prime therapeutic targets in the treatment of MM. In the present report, we have investigated the effect of Brucein D (BD) on Akt-driven signaling events in MM cells. BD (300 nM) substantially inhibited cell viability and imparted growth-inhibitory effects in U266 cells as evidenced by cell viability assays and flow cytometric analysis. Effect of BD on cell viability was evaluated by MTT assay. Apoptotic cells and cell cycle arrest by BD were analyzed by flow cytometer. The results of the TUNEL assay and western blotting showed that BD induces apoptosis of MM cells by activating caspase-8 and 9 with subsequent reduction in the expression of antiapoptotic proteins (Bcl-2, Bcl-xl, survivin, cyclin D1, COX-2, VEGF, MMP-9). Analysis of activated kinases by Phospho-Kinase Array Kit revealed that Akt, p70S6K, HSP60, p53, and WNK1 were strongly expressed in untreated cells and BD treatment reversed this effect. Using transfection experiments, AKT depletion led to a decrease in phosphorylation of Akt, mTOR, p70S6K, and WNK. However, Akt overexpression led to increase in phosphorylation of these proteins. Depletion of Akt potentiated the apoptosis-inducing effect of BD whereas overexpression displayed resistance to BD-induced apoptosis suggesting the role of Akt in chemoresistance. Taken together, BD mitigates Akt-dependent signaling pathways in MM cells to impart its anticancer activity.

Novel 1,2,5-Trisubstituted Benzimidazoles Potentiate Apoptosis by Mitochondrial Dysfunction in Panel of Cancer Cells.

Synthetic small molecules have been very effective in decimating cancer cells by targeting various aberrantly overexpressed oncogenic proteins. These small molecules target proteins involved in cell cycle regulation, cell division, migration, invasion, angiogenesis, and other regulatory proteins to induce apoptosis in cancer cells. In this study, we have synthesized a novel 1,2,5-trisubstituted benzimidazole chemical library of small molecules and unveiled their anticancer potential against a panel of cancer cell lines such as Jurkat, K-562, MOLT-4, HeLa, HCT116, and MIA PaCa-2 cancer cells. The MTT assay and Trypan blue dye exclusion assay clearly unveiled the cytotoxic effect of methyl 1-benzyl-2-(4-fluoro-3-nitrophenyl)-1H-benzo[d]imidazole-5-carboxylate (TJ08) and its potential to induce apoptosis with effective IC50 of 1.88 ± 0.51, 1.89 ± 0.55, 2.05 ± 0.72, 2.11 ± 0.62, 3.04 ± 0.8, and 3.82 ± 0.25 µM against Jurkat, K562, MOLT-4, HeLa, HCT116, and MIA PaCa-2 cancer cell lines, respectively. Altered mitochondrial membrane potential was observed in HeLa, HCT116, and Jurkat cells due to TJ08 treatment, which was unveiled by JC10 staining. Induction of early and late apoptosis by TJ08 treatment was also unveiled by apoptotic analysis and immunofluorescence imaging. Cell cycle analysis distribution confirms the accumulation of cells in the S-phase in a dose-dependent manner.