Dihydropyrimidinones as potent anticancer agents: Insight into the structure-activity relationship.

Cancer is a serious disease that has been around for a long time but currently has no sustainable solution. Several medications currently available offer an opportunity for the manifestation of cancer treatment; however, the "search for better" has led to the development and study of a variety of new scaffolds. Dihydropyrimidinones (DHPMs) are a privileged scaffold, prominent for their versatile range of biological activities. In recent years, the anticancer potential of these unsaturated pyrimidine ring systems has been traversed, along with their synthesis methods and the interlinked mechanisms leading to the anticancer activity. This review summarizes the structure-activity relationship of DHPMs as potential anticancer agents. This study is a short review of their synthesis, mechanism of action, and structure-activity relationships (SARs) that are answerable for the anticancer activity of DHPMs and have been thoroughly researched and assessed.

Structure based exploration of mitochondrial alpha carbonic anhydrase inhibitors as potential leads for anti-obesity drug development.

BACKGROUND: Obesity has emerged as a major health challenge globally in the last two decades. Dysregulated fatty acid metabolism and de novo lipogenesis are prime causes for obesity development which ultimately trigger other co-morbid pathological conditions thereby risking life longevity. Fatty acid metabolism and de novo lipogenesis involve several biochemical steps both in cytosol and mitochondria. Reportedly, the high catalytically active mitochondrial carbonic anhydrases (CAVA/CAVB) regulate the intercellular depot of bicarbonate ions and catalyze the rapid carboxylation of pyruvate and acetyl-co-A to acetyl-co-A and malonate respectively, which are the precursors of fatty acid synthesis and lipogenesis. Several in vitro and in vivo investigations indicate inhibition of mitochondrial carbonic anhydrase isoforms interfere in the functioning of pyruvate, fatty acid and succinate pathways. Targeting of mitochondrial carbonic anhydrase isoforms (CAVA/CAVB) could thereby modulate gluconeogenetic as well as lipogenetic pathways and pave way for designing of novel leads in the development pipeline of anti-obesity medications. METHODS: The present review unveils a diverse chemical space including synthetic sulphonamides, sulphamates, sulfamides and many natural bioactive molecules which selectively inhibit the mitochondrial isoform CAVA/CAVB with an emphasis on major state-of-art drug design strategies. RESULTS: More than 60% similarity in the structural framework of the carbonic anhydrase isoforms has converged the drug design methods towards the development of isoform selective chemotypes. While the benzene sulphonamide derivatives selectively inhibit CAVA/CAVB in low nanomolar ranges depending on the substitutions on the phenyl ring, the sulpamates and sulpamides potently inhibit CAVB. The virtual screening and drug repurposing methods have also explored many non-sulphonamide chemical scaffolds which can potently inhibit CAVA. CONCLUSION: The review could pave way for the development of novel and effective anti-obesity drugs which can modulate the energy metabolism.

Facile Green Synthesis of Iron Oxide Nanoparticles and Their Impact on Cytotoxicity, Antioxidative Properties and Bactericidal Activity.

Background: Bioreductive processes are quite potent, effective and affordable for the synthesis of green nanoparticles (NPs), as compared to the physical and chemical methods. The present study aimed to evaluate the bactericidal, antioxidative and anticancer activity of turmeric rhizome-iron oxide nanoparticles (FeONPs) derived from the turmeric rhizome (Curcuma amada) using ferric chloride as a precursor. Methods: With focusing on the manufacture of FeONPs via green approach, we characterized the NPs using FTIR, FT-Vis, DLS, and UV-Vis spectroscopy. The produced particles were tested for antibacterial, antioxidant, and anticancer properties. The synthesized NPs were also examined using the MDA-MB-231 human epithelial breast cancer cell line and NCI-60 cancer cell lines. Results: The antioxidant activity of TR-FeONPs was concentration-dependent. The scavenging activity of TR-FeONPs was 76.09% at a concentration of 140 µg/ml. Using different concentrations of TR-FeONPs in the MTT assay against the MDA-MB-231 cell line indicated a reduction of less than 50% in cell viability at 125 µg/ml. Moreover, TR-FeONPs exhibited an effective bactericidal property. The gTR-FeONPs synthesized bioreductively were found to be effective in renal cancer, UO-31 cell line, with GI50 value of 66.64%. Conclusion: Our study showcases a sustainable method based on green chemistry principles to produce FeONPs utilizing turmeric rhizome. We anticipate that the FeONPs produced through this biosynthesis process could serve as a promising drug delivery system in cancer treatment and as an effective antimicrobial agent against various diseases.

Antibacterial and cytotoxicity studies of pyrrolo-based organic scaffolds and their binding interaction with bovine serum albumin.

Two pyrrolo-based compounds, 1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (L1) and 1H-pyrrolo[3,2-c]pyridine-4-carboxylic acid (L2), were employed for the detection of bovine serum albumin (BSA) by UV-Vis and fluorescence spectroscopic methods in phosphate buffer solution (pH = 7). In the presence of L1 and L2, the fluorescence emission of BSA at 340 nm was quenched and concomitantly a red-shifted emission band appeared at 420 nm (L1)/450 nm (L2). The fluorescence spectral changes indicate the protein-ligand complex formation between BSA and L1/L2. An isothermal titration calorimetry (ITC) experiment was conducted to determine the binding ability between BSA and L1/L2. The binding constants are found to be 4.45 ± 0.22 × 104 M-1 for L1 and 2.29 ± 0.11 × 104 M-1 for L2, respectively. The thermodynamic parameters were calculated from ITC measurements (i.e. ∆rH = -40 ± 2 kcal/mol, ∆rG = -4.57 ± 0.22 kcal/mol and -T∆rS = 35.4 ± 1.77 kcal/mol), which indicated that the protein-ligand complex formation between L1/L2 with BSA is mainly due to the electrostatic interactions. The protein-ligand interactions were studied by performing molecular docking. Further, the antibacterial assay of L1 and L2 was conducted against gram-positive and gram-negative bacterial strains in an effort to address the difficulties caused by the co-occurrence of antimicrobial and multidrug-resistant bacteria. E. coli and S. aureus were significantly inhibited by L1 and L2. The L1 exhibits 13, 12 and 15 mm, whereas L2 exhibits a 2, 3 and 5 mm zone of inhibition against S. aureus, S. pyogenes and E. coli, respectively. In silico molecular docking of L1 and L2 was performed with bacterial DNA gyrase to establish the intermolecular interactions. Finally, the in vitro cytotoxicity activities of the ligands L1 and L2 have been carried out using drosophila.

Protein interactions, molecular docking, antimicrobial and antifungal studies of terpyridine ligands.

Resistance to antibiotics/antibacterials/antifungals in pathogenic microbes has been developing over the past few decades and has recently become a commonplace public-health peril. Thus, alternative nontoxic potent antibiotic agents are covertly needed to control antibiotic-resistant outbreaks. In an effort to combat the challenges posed by the co-occurrence of multidrug resistance, two terpyridine ligands 4'-(4-N,N'-dimethylaminophenyl)-2,2':6',2″-terpyridine (L1) and 4'-(4-tolyl)-2,2':6',2″-terpyridine (L2) have been designed, prepared and confirmed their structure by spectral studies. Thereafter, antimicrobial assay was performed against gram positive and negative bacterial strains along with fungal strains. Both compounds L1 and L2 exhibited remarkable inhibitory activities against bacteria, Escherichia coli and Staphylococcus aureus at MIC values 6.25 and 3.125 µg/ml, respectively. In addition, in silico molecular docking studies were ascertained with bacterial DNA gyrase and fungal demethylase. Furthermore, both L1 and L2 could bind Bovine Serum Albumin (BSA) protein and binding interaction has been studied with the help of UV-Visible and fluorescence spectroscopy. While fluorescence of BSA unperturbed in the presence of L2, an addition of L1 to the solution of BSA resulted significant quenching. The binding constant calculations at different temperature confirmed that the fluorescence quenching between BSA and L1 is predominantly static in nature. The toxicity of L1 and L2 was checked using Drosophila melanogaster. The toxicity analysis suggest both the dyes are non-cytotoxic in nature.Communicated by Ramaswamy H. Sarma.