Novel chiral phthalimides: Antimicrobial evaluation and docking study against Acinetobacter baumannii's OmpA protein.

Antibiotics have been a vital component in the fight against microbial diseases for over 75 years, saving countless lives. However, the global rise of multi-drug-resistance (MDR) bacterial infections is pushing us closer to a post-antibiotic era where common infections may once again become lethal. To combat MDR Acinetobacter baumannii, we investigated chiral phthalimides and used molecular docking to identify potential targets. Outer membrane protein A (OmpA) is crucial for A. baumannii resistant to antibiotics, making it a pathogen of great concern due to its high mortality rate and limited treatment options. In this study, we evaluated three distinct compounds against the OmpA protein: FIA (2-(1,3-dioxoindolin-2yl)-3-phenylpropanoic acid), FIC (2-(1,3-dioxoindolin-2yl)-4-(methylthio) butanoic acid), and FII (3-(1,3-dioxoindolin-2yl)-3-phenylpropanoic acid). Molecular docking results showed that these three compounds exhibited strong interactions with the OmpA protein. Molecular dynamics (MD) simulation analysis further confirmed the stability and binding efficacy of these compounds with OmpA. Their antimicrobial activities were assessed using the agar well diffusion method, revealing that FIA had an optimal zone of inhibition of 24 mm. Additionally, the minimum inhibitory concentrations (MIC) of these compounds were determined, demonstrating their bactericidal properties against A. baumannii, with MICs of 11 µg/µL for FIA, 46 µg/µL for FIC, and 375 µg/µL for FII. In vitro cytotoxicity data indicated that none of the three compounds were hemolytic when exposed to human red blood cells. This finding is particularly significant as it highlights the superior efficacy of FIA against A. baumannii compared to the other compounds. With thorough pharmacokinetic validations, these chiral phthalimides are promising alternative therapeutic options for treating infections caused by A. baumannii, offering new hope in the face of rising antibiotic resistance.

Mentha arvensis oil exhibits repellent acute toxic and antioxidant activities in Nauphoeta cinerea.

Mentha arvensis is an herbaceous plant commonly known as peppermint or Japanese mint. This study investigated the toxic potential and repellent efficacy of M. arvensis essential oil (MaEO) at varying concentrations (15.625-250 mg/mL) in Nauphoeta cinerea, along with its impact on biochemical parameters in N. cinerea. The potential of the major compounds as a new analgesic target was investigated using molecular docking. The essential oil was analyzed by gas Chromatography-mass spectrometry (GC-MS) and the toxic potential, repellent property, and changes in lipid peroxidation (LPO) levels were evaluated as markers of oxidative stress. GC-MS results revealed that the main components were oxygenated monoterpenes such as menthol (71.31%), mentone (13.34%) and isomentone (5.35%). MaEO significantly reduced lipid peroxidation (LPO), the levels of non-protein thiols and iron(II) at the concentration of 125 mg/mL in N. cinerea. Furthermore, the major components, L-(-)-Menthol and menthone demonstrated high gastrointestinal absorption and high affinity with the target protein, suggesting possible links that contribute to the analgesic effect of MaEO.

Babesia bigemina and Theileria annulata infections in cattle: molecular detection, phylogenetic analysis, and assessment of risk factors.

Babesia bigemina and Theileria annulata are tick-borne protozoans that cause piroplasmosis in cattle, resulting in huge damages to the livestock industry. The prevalence of these infections depends on various intrinsic and extrinsic risk factors. In Pakistan, there is no information regarding the molecular characterization of Babesia bigemina and the risk factors associated with piroplasmosis. This study aimed to molecularly characterize Babesia spp. and Theileria spp. infecting various cattle breeds in Khyber Pakhtunkhwa, Pakistan, and to shed light on risk factors associated with these infections. Altogether, 219 blood samples were collected from various symptomatic cattle breeds, including Holstein Friesian (65.3%; 143/219), Jersey (21.5%; 47/219) and Sahiwal (13.2%; 29/219). Isolated genomic DNA from these blood samples was used in PCR for the amplification of the 18S rRNA fragment of apicomplexan parasites. Obtained 18S rDNA sequences from cattle hosts showed 99.5% identity with B. bigemina, or 100% with T. annulata. Having an overall infection rate of 61.6% (135/219), the highest infection rate was recorded for T. annulata (43.8%; 95/219), followed by B. bigemina (18.3%; 40/219). Phylogenetic analysis of 18S rDNA sequences revealed that B. bigemina clustered with corresponding species reported from Bolivia, and South Africa, while T. annulata grouped with same species from Italy, India, and Turkey. Among the different risk factors, the breed, season, and tick infestation were found to have a significant (P < 0.05) association with the piroplasmid infections. The information obtained in this study can be employed for effective surveillance and control of babesiosis and theileriosis in Pakistan. In addition to confirming our previous molecular detection of T. annulata in cattle, this study provides the first molecular surveillance and phylogenetic position of B. bigemina and associated risk factors in the study region.

Molecular detection of Anaplasma bovis, Candidatus Anaplasma boleense and Rickettsia spp. in ticks infesting small ruminants.

Anaplasma spp. and Rickettsia spp. are intracellular vector-borne pathogens and harbored by a wide range of ticks and vertebrate hosts. Aim of this study was to molecularly characterize Anaplasma spp. and Rickettsia spp. in different ticks collected from livestock hosts in nine districts of Khyber Pakhtunkhwa (KP), Pakistan. In total, 862 ticks were collected from cattle, goats and sheep. Highest tick's infestation was observed on cattle 56.14% (32/57), followed by goats 45.45% (40/88), and sheep 42.05% (45/107). Rhipicephalus microplus (305/862, 35.38%) was predominant species, followed by Haemaphysalis sulcata (243/862, 28.19%), Hyalomma anatolicum (133/862, 15.42%), Haemaphysalis bispinosa (120/862, 13.92%), and Hyalomma kumari (61/862, 7.07%). A subset of 135 ticks were screened for Anaplasma spp. and Rickettsia spp. based on the amplification of partial 16 S rDNA and outer-membrane protein A (ompA) fragments, respectively. In total, 16 ticks (11.85%) were positive for Anaplasma spp. and Rickettsia spp. Obtained 16 S rDNA sequences for Anaplasma spp. detected in Ha. bispinosa and Ha. sulcata showed 99.98% identity with Anaplasma bovis, while other detected in Rh. microplus showed 99.84% identity with Candidatus Anaplasma boleense. Similarly, detected ompA sequence in Ha. sulcata showed 100% identity with Rickettsia sp. and 97.93% with Rickettsia slovaca, and another sequence detected in Rh. microplus showed 100% identity with Candidatus Rickettsia shennongii. In phylogenetic trees, these sequences clustered with corresponding species from Pakistan, China, Turkey, South Korea, South Africa, and Herzegovina. This is the first study reporting detection of A. bovis in Ha. bispinosa and Ha. sulcata, Ca. A. boleense in Rh. microplus collected from goats, and R. slovaca-like in Ha. sulcata. Our results enforce the need for regular surveillance of Rickettsiales in hard ticks infesting livestock in the region.

Bioactive plant waste components targeting oral bacterial pathogens as a promising strategy for biofilm eradication.

The significance of this study lies in its exploration of bioactive plant extracts as a promising avenue for combating oral bacterial pathogens, offering a novel strategy for biofilm eradication that could potentially revolutionize oral health treatments. Oral bacterial infections are common in diabetic patients; however, due to the development of resistance, treatment options are limited. Considering the excellent antimicrobial properties of phenolic compounds, we investigated them against isolated oral pathogens using in silico and in vitro models. We performed antibiogram studies and minimum inhibitory concentration (MIC), antibiofilm, and antiquorum sensing activities covering phenolic compounds. Bacterial strains were isolated from female diabetic patients and identified by using 16S rRNA sequencing as Pseudomonas aeruginosa, Bacillus chungangensis, Bacillus paramycoides, and Paenibacillus dendritiformis. Antibiogram studies confirmed that all strains were resistant to most tested antibiotics except imipenem and ciprofloxacin. Molecular docking analysis revealed the significant interaction of rutin, quercetin, gallic acid, and catechin with transcription regulator genes 1RO5, 4B2O, and 5OE3. All tested molecules followed drug-likeness rules except rutin. The MIC values of the tested compounds varied from 0.0625 to 0.5 mg/mL against clinical isolates. Significant antibiofilm activity was recorded in the case of catechin (73.5% ± 1.6% inhibition against B. paramycoides), cinnamic acid (80.9% ± 1.1% inhibition against P. aeruginosa), and vanillic acid and quercetin (65.5% ± 1.7% and 87.4% ± 1.4% inhibition, respectively, against B. chungangensis) at 0.25-0.125 mg/mL. None of the phenolic compounds presented antiquorum sensing activity. It was, therefore, concluded that polyphenolic compounds may have the potential to be used against oral bacterial biofilms, and further detailed mechanistic investigations should be performed.

Investigation of the role of Cremophor RH 40 and Cremophor EL in the inhibition of efflux pump of Pseudomonas aeruginosa.

Background: There is increasing emphasis on restoring the efficacy of existing antibiotics instead of developing new ones. Objectives: This study aimed to determine the role of Cremophor EL and Cremophor RH40 in the inhibition of efflux pumps in MDR Pseudomonas aeruginosa strains. Methods: Efflux pump-active MDR strains of P. aeruginosa were identified and confirmed by flow cytometry. The identified efflux-active strains were further subjected to determination of the MIC of ciprofloxacin and the synergistic role of non-ionic surfactants (Cremophor EL and Cremophor RH40) along with ciprofloxacin. Results: Out of 30 samples, 6 strains displayed high efflux pump activity. Both Cremophor EL and Cremophor RH40 showed efflux pump inhibitory roles. A 4-fold reduction in the MIC values of ciprofloxacin was observed when Cremophor EL was used along with ciprofloxacin, while a 6-fold reduction was observed when Cremophor RH40 was used along with ciprofloxacin. Both compounds showed synergistic effects with ciprofloxacin, ticarcillin and meropenem when used in a 24-well plate efflux pump inhibitory assay. Conclusion: The inhibition of the efflux pump of MDR Pseudomonas aeruginosa by non-ionic surfactants, namely, Cremophor RH40 and Cremophor EL, provided the best strategy to restore the efficacy of ciprofloxacin.

Design, synthesis, molecular docking study, and α-glucosidase inhibitory evaluation of novel hydrazide-hydrazone derivatives of 3,4-dihydroxyphenylacetic acid.

A series of novel Schiff base derivatives (1-28) of 3,4-dihydroxyphenylacetic acid were synthesized in a multi-step reaction. All the synthesized Schiff bases were obtained in high yields and their structures were determined by 1HNMR, 13CNMR, and HR-ESI-MS spectroscopy. Except for compounds 22, 26, 27, and 28, all derivatives show excellent to moderate α-glucosidase inhibition. Compounds 5 (IC50 = 12.84 ± 0.52 µM), 4 (IC50 = 13.64 ± 0.58 µM), 12 (IC50 = 15.73 ± 0.71 µM), 13 (IC50 = 16.62 ± 0.47 µM), 15 (IC50 = 17.40 ± 0.74 µM), 3 (IC50 = 18.45 ± 1.21 µM), 7 (IC50 = 19.68 ± 0.82 µM), and 2 (IC50 = 20.35 ± 1.27 µM) shows outstanding inhibition as compared to standard acarbose (IC50 = 873.34 ± 1.67 µM). Furthermore, a docking study was performed to find out the interaction between the enzyme and the most active compounds. With this research work, 3,4-dihydroxyphenylacetic acid Schiff base derivatives have been introduced as a potential class of α-glucosidase inhibitors that have remained elusive till now.

Synthesis of novel hydrazide Schiff bases with anti-diabetic and anti-hyperlipidemic effects: in-vitro, in-vivo and in-silico approaches.

The increasing global incidence of non-insulin-dependent diabetes mellitus (NIDDM) necessitates innovative therapeutic solutions. This study focuses on the design, synthesis and biological evaluation of Schiff base derivatives from 2-bromo-2-(2-chlorophenyl) acetic acid, particularly hydrazone compounds 4a and 4b. Both in-vitro and in-vivo assays demonstrate these derivatives' strong antidiabetic and anti-hyperlipidemic properties. In a 15-d experiment, we administered 4a and 4b at doses of 2.5 and 5 mg/kg body weight, which effectively improved symptoms of alloxan-induced diabetes in mice. These symptoms included weight loss, increased water consumption and high blood glucose levels. The compounds also normalized abnormal levels of total cholesterol (TC), triacylglycerol (TG) and low-density lipoprotein cholesterol (LDL-C), while raising the levels of high-density lipoprotein cholesterol (HDLC). Computational analysis showed that these compounds effectively inhibited the α-glucosidase enzyme by interacting with key catalytic residues, specifically Asp214 and Asp349. These computational results were confirmed through in-vitro tests, where 4a and 4b showed strong α-glucosidase inhibitory activity, with IC50 values of 0.70 ± 0.11 and 10.29 ± 0.30 µM, respectively. These compounds were more effective than the standard drug, acarbose, which had an IC50 value of 873.34 ± 1.67 µM. Mechanistic studies further indicated competitive inhibition, reinforcing the therapeutic potential of 4a and 4b for NIDDM treatment.Communicated by Ramaswamy H. Sarma.

Chiral phthalimides against penicillin-binding protein 2a of methicillin-resistant Staphylococcus aureus: molecular docking and in vitro analysis.

Staphylococcus aureus (S. aureus) is a commensal bacterium and an opportunistic pathogen causing a wide variety of infections ranging from localized skin and soft tissue infections to life-threatening severe bacteremia, osteomyelitis, endocarditis, atopic dermatitis, prosthetic joint infection, staphylococcal food poisoning, medical device-related infections, and pneumonia. It is attributed to an acquired resistant gene, mecA, encoding penicillin-binding protein 2a (PBP2a). PBP2a is an essential protein responsible for the resistivity of methicillin-resistant S. aureus (MRSA) to various beta-lactam antibiotics. The antimicrobial treatment alternatives for MRSA are increasingly limited. Therefore, developing alternative therapeutic options for its treatment is the need of the day. Phthalimides and their N-substituted derivatives are of biological importance as they possess extensive biological and pharmaceutical properties and can serve as an excellent therapeutic option for MRSA. This study uses three chiral phthalimides (FIA, FIB, and FIC) to check their in silico and in vitro inhibitory effects. Molecular docking of these chiral phthalimides against PBP2a of MRSA was performed initially. After promising results, these novel compounds were screened through the agar-well diffusion method and micro-broth dilution assay to investigate their in vitro inhibitory activities with FIB being the strongest anti-staphylococcal agent yielding a 21 mm zone of inhibition and a minimum inhibitory concentration (MIC) of 0.022 ug, respectively. The zones of inhibition obtained through the in vitro activity showed that these chiral phthalimides possess substantial anti-MRSA activities and have the potential to be considered as alternative chemotherapeutics to treat the infections caused by MRSA after the confirmation of their cytotoxic and pharmacokinetic studies.

Punicalagin improves inflammation and oxidative stress in rat model of pelvic inflammatory disease.

Pelvic inflammatory disease (PID) is one of the major public health concerns accounting for 30% of infertility and 50% of ectopic pregnancy cases due to severe inflammation and fibrosis. Punicalagin® are known to exhibit potent anti-inflammatory activity. The aim of this study was to demonstrate the anti-inflammatory and antioxidant effects of Punicalagin®, against pelvic inflammatory disease in rats. Female Sprague Dawley rats (n = 24) were divided into 6 groups (n = 4) as control, PID, prophylactic (low dose and high dose) and therapeutic group (low dose and high dose). PID model was constructed by implanting the rat cervix with mixed microbe (Escherichia Coli and Staphylococcus Aureus) solution. Prophylactic group was gavaged with 3 mg/kg (low dose) and 6 mg/kg (high dose) Punicalagin® daily starting one day before PID induction and therapeutic group was gavaged with 3 mg/kg (low dose) and 6 mg/kg (high dose) Punicalagin® daily starting 1 day after confirmation of PID model. Rats were sacrificed at the end of experiment and samples from upper genital tract were collected for ELISA, antioxidant assay and histopathological examination. According to results, obvious signs of inflammation and oxidative stress including infiltration of neutrophils and significantly raised levels of cytokines, and oxidative stress markers were observed in PID group when compared to control group. Punicalagin® significantly decreased the levels of IL-1ß, catalase and lipid peroxidation in both prophylactic and therapeutic groups when compared to PID group. Punicalagin® also decreased the infiltration of leucocytes in uterus of prophylactic and therapeutic group when compared to PID group, as determined by histological examination. On basis of these results, we concluded that Punicalagin® showed anti-inflammatory and antioxidant potential in rat model of pelvic inflammatory disease and could be used as possible therapeutic agent in treatment of PID.

Synthesis, molecular docking and DFT analysis of novel bis-Schiff base derivatives with thiobarbituric acid for α-glucosidase inhibition assessment.

A library of novel bis-Schiff base derivatives based on thiobarbituric acid has been effectively synthesized by multi-step reactions as part of our ongoing pursuit of novel anti-diabetic agents. All these derivatives were subjected to in vitro α-glucosidase inhibitory potential testing after structural confirmation by modern spectroscopic techniques. Among them, compound 8 (IC50 = 0.10 ± 0.05 µM), and 9 (IC50 = 0.13 ± 0.03 µM) exhibited promising inhibitory activity better than the standard drug acarbose (IC50 = 0.27 ± 0.04 µM). Similarly, derivatives (5, 6, 7, 10 and 4) showed significant to good inhibitory activity in the range of IC50 values from 0.32 ± 0.03 to 0.52 ± 0.02 µM. These derivatives were docked with the target protein to elucidate their binding affinities and key interactions, providing additional insights into their inhibitory mechanisms. The chemical nature of these compounds were reveal by performing the density functional theory (DFT) calculation using hybrid B3LYP functional with 6-311++G(d,p) basis set. The presence of intramolecular H-bonding was explored by DFT-d3 and reduced density gradient (RGD) analysis. Furthermore, various reactivity parameters were explored by performing TD-DFT at CAM-B3LYP/6-311++G(d,p) method.

Response to carvacrol monoterpene in the emergence of Allium cepa L. seeds exposed to salt stress.

Abiotic stresses including sodium chloride (NaCl) are known to negatively affect plant physiology and seed germination by inducing a delay in establishing seedling emergence. The monoterpene carvacrol is the major component of several aromatic plants and seems to interfere with germination and seedling growth. In this study, we investigated whether treatment with carvacrol attenuates the effects of NaCl on the germination and development of Allium cepa, where biochemical parameters were also analyzed. The results showed that the Emergency Speed Index (ESI) was near to 2.0 in the control group. The groups NaCl, carvacrol alone, and in co-treatment with NaCl exhibited an ESI below 0.8, being significantly smaller when compared to the control. NaCl + carvacrol significantly inhibited seed emergence in relation to the NaCl group. Only the content of malondialdehyde was significantly altered by NaCl.

Synthesis of new bis(dimethylamino)benzophenone hydrazone for diabetic management: In-vitro and in-silico approach.

Inhibiting α-glucosidase is a reliable method for reducing blood sugar levels in diabetic individuals. Bis(dimethylamino)benzophenone derivatives 1-27 were synthesized from bis(dimethylamino)benzophenone via two-step reaction. Different spectroscopic techniques, including EI-MS and 1H NMR, were employed to characterize all synthetic derivatives. The elemental composition of synthetic compounds was confirmed by elemental analysis and results were found in agreement with the calculated values. The synthetic compounds 1-27 were evaluated for α-glucosidase inhibitory activity, except five compounds all derivatives showed good to moderate inhibitory potential in the range of IC50 = 0.28 ± 2.65 - 0.94 ± 2.20 µM. Among them, the most active compounds were 5, 8, 9, and 12 with IC50 values of 0.29 ± 4.63, 0.29 ± 0.93, 0.28 ± 3.65, and 0.28 ± 2.65, respectively. Furthermore, all these compounds were found to be non-toxic on human fibroblast cell lines (BJ cell lines). Kinetics study of compounds 8 and 9 revealed competitive type of inhibition with Ki values 2.79 ± 0.011 and 3.64 ± 0.012 µM, respectively. The binding interactions of synthetic compounds were also confirmed through molecular docking studies that indicated that compounds fit well in the active site of enzyme. Furthermore, a total of 30ns MD simulation was carried out for the most potent complexes of the series. The molecular dynamics study revealed that compound-8 and compound-12 were stable during the MD simulation.

Synthesis, characterization, Hirshfeld surface analysis, antioxidant and selective ß-glucuronidase inhibitory studies of transition metal complexes of hydrazide based Schiff base ligand.

The synthesis of N'-[(4-hydroxy-3-methoxyphenyl)methylidene] 2-aminobenzohydrazide (H-AHMB) was performed by condensing O-vanillin with 2-aminobenzohydrazide and was characterized by FTIR, high resolution ESI(+) mass spectral analysis, 1H and 13C-NMR. The compound H-AHMB was crystallized in orthorhombic Pbca space group and studied for single crystal diffraction analysis. Hirshfeld surface analysis was also carried out for identifying short interatomic interactions. The major interactions H…H, O…H and C…H cover the Hirshfeld surface of H-AHMB. The metal complexes [M(AHMB)n] where M = Co(II), Ni(II), Cu(II) and Zn(II) were prepared from metal chlorides and H-AHMB ligand. The bonding was unambigously assigned using FTIR and UV/vis analysis. The synthesized ligand H-AHMB and its metal complexes were studied for ß-glucuronidase enzyme inhibition. Surprisingly the metal complexes were found more active than the parent ligand and even the standard drug. Zn-AHMB shown IC50 = 17.3 ± 0.68 µM compared to IC50 = 45.75 ± 2.16 µM shown by D-saccharic acid-1,4-lactone used as standard. The better activity by Zn-AHMB implying zinc based metallodrug for the treatment of diseases associated with ß-glucuronidase enzyme. The DPPH radical scavenging activities were also studied for all the synthesized compounds. The Co-AHMB complex with IC50 = 98.2 ± 1.78 µM was the only candidate to scavenge the DPPH free radicals.

Novel benzimidazole derivatives as effective inhibitors of prolyl oligopeptidase: synthesis, in vitro and in silico analysis.

Background: This research aims to discover novel derivatives having potential therapeutic applications in treating conditions related to prolyl oligopeptidase (POP) dysfunction. Method: Novel benzimidazole derivatives have been synthesized, characterized and screened for their in vitro POP inhibition. Results: All these derivatives showed excellent-to-good inhibitory activities in the range of IC50 values of 3.61 ± 0.15 to 43.72 ± 1.18 µM, when compared with standard Z-prolyl-prolinal. The docking analysis revealed the strong interactions between our compounds and the target enzyme, providing critical insights into their binding affinities and potential implications for drug development. Conclusion: The significance of these compounds in targeting POP enzyme offers promising prospects for future research in the field of neuropharmacology.

Exploring the synthesis, structure, spectroscopy and biological activities of novel 4-benzylidene-1-(2-(2,4-dichloro phenyl)acetyl) thiosemicarbazide derivatives: An integrated experimental and theoretical investigation.

Background: Novel α-amylase inhibitors play a crucial role in managing diabetes and obesity, contributing to improved public health by addressing these challenging and prevalent conditions. Moreover, the synthesis of anti-oxidant agents is essential due to their potential in combating oxidative stress-related diseases and promoting overall health. Objective: Synthesis of thoisemicarbazone derivatives of 2,4-dichlorophenyl acetic acid and to screened them for their biological activities. Method: Thiosemicarbazone derivatives (4-13) were synthesized by refluxing 2,4-dichlorophenyl acetic acid with sulfuric acid in ethanol to get the ester (2), which was further refluxed with thiosemicarbazide to get compound (3). Finally, different aromatic aldehydes were refluxed with compound (3) in ethanol in catalytic amount of acetic acid to obtained the final products (4-13). Using modern spectroscopic techniques including HR-ESI-MS, 13C-, and 1H NMR, the structures of the created derivatives were confirmed. Results: The synthesized derivatives showed excellent to good inhibitory activity in the range of IC50 values of 4.95 ± 0.44 to 69.71 ± 0.05 µM against α-amylase enzyme when compared to standard drug acarbose (IC50 = 21.55 ± 1.31 µM). In case of iron chelating activity, these products showed potent activity better than standard EDTA (IC50 = 66.43 ± 1.07 µM) in the range of IC50 values of 22.43 ± 2.09 to 61.21 ± 2.83 µM. However, the obtained products also show excellent to good activity in the range of IC50 values of 28.30 ± 1.17 to 64.66 ± 2.43 µM against hydroxyl radical scavenging activity when compared with standard vitamin C (IC50 = 60.51 ± 1.02 µM). DFT used to calculate different reactivity factors including ionization potential, electronegativity, electron affinity, chemical softness, and chemical hardness were calculated using frontier molecular orbital (FMO) computations. The molecular docking studies for the synthesized derivatives with α-amylase were carried out using the AutoDock Vina to understand the binding affinities with active sites of the protein.

Inhibition of Acetylcholinesterase with Novel 1, 3, 4, Oxadiazole Derivatives: A Kinetic, In Silico, and In Vitro Approach.

Alzheimer's disease (AD) is a neurological disease that disturbs the memory, thinking skills, and behavior of the affected person. AD is a complex disease caused by the breakdown of acetylcholine via acetylcholinesterase (AChE). The present study aimed to assess the synthetic inhibitors of AChE that could be used to treat AD. For this purpose, synthetic compounds of oxadiazole derivatives (15-35) were evaluated and identified as promising inhibitors of AChE, exhibiting IC50 varying between 41.87 ± 0.67 and 1580.25 ± 0.7 µM. The kinetic parameters indicated that all the studied compounds bind to the allosteric site and decrease the efficiency of the AChE enzyme. In silico docking analysis showed that the majority of the compounds interact with the anionic subsite and Per-Arnt-Sim domain of AChE and are stabilized by various bonds including π-π and hydrogen bonding. The stability of the most potent compounds 16 and 17 with AChE interaction was confirmed by molecular dynamics simulations. Moreover, all compounds exhibited concentration-dependent calcium (Ca2+) antagonistic and spasmolytic activities. Among the whole series of oxadiazole derivatives, compounds 16 and 17 displayed the highest activities on spontaneous and potassium (K+)-induced contraction. Therefore, the AChE inhibitory potential, cytotoxicity safe profile, and Ca2+ antagonistic ability of these compounds make them potential therapeutic agents against AD and its associated problems in the future.

Genotoxicity and cytotoxicity potential of organoselenium compounds in human leukocytes in vitro.

In the current work, cytotoxicity and genotoxicity of different organoselenium compounds were examined using Trypan blue exclusion and alkaline comet assays with silver staining respectively. Leukocytes were subjected to a 3-hour incubation with organoselenium compounds at concentrations of 1, 5, 10, 25, 50, and 75 µM, or with the control vehicle (DMSO), at a temperature of 37 °C. The viability of the cells was evaluated using the Trypan blue exclusion method, while DNA damage was analyzed through the alkaline comet assay with silver staining. The exposure of leukocytes to different organoselenium compounds including i.e. (Z)-N-(pyridin-2-ylmethylene)-1-(2-((2-(1-((E)-pyridin-2-ylmethyleneamino)ethyl)phenyl)diselanyl)phenyl)ethanamine (C1), 2,2'(1Z,1'E)-(1,1'-(2,2'-diselanediylbis(2,1-phenylene))bis(ethane-1,1-diyl)) bis(azan-1-yl-1-ylidene)bis -methan-1-yl-1-ylidene)diphenol (C2), and dinaphthyl diselenide (NapSe)2, At concentrations ranging from 1 to 5 µM, no significant DNA damage was observed, as indicated by the absence of a noteworthy increase in the Damage Index (DI). Our results suggest that the organoselenium selenium compounds tested were not genotoxic and cytotoxic to human leukocytes in vitro at lower concentration. This study offers further insights into the genotoxicity profile of these organochalcogens in human leukocytes. Their genotoxicity and cytotoxicity effects at higher concentration are probably mediated through reactive oxygen species generation and their ability to catalyze thiol oxidation.

The Effectiveness of Polypill for the Prevention of Cardiovascular Disease: A Meta-Analysis of Randomized Controlled Trials.

A significant global health concern, cardiovascular disease (CVD) is characterized by a rising prevalence and accompanying mortality rates. It is crucial to implement primary and secondary prevention strategies, particularly in resource-scarce settings. Polypills, which combine blood pressure, cholesterol, and homocysteine drugs, hold significant potential for lowering the risk of CVD. This study follows PRISMA meta-analysis guidelines. Two researchers conducted an extensive literature search. Inclusion criteria encompassed RCT design, polypill use, a four-week duration, and one meta-analysis outcome. Primary outcomes included MACE and CV mortality, while secondary outcomes encompassed SBP and LDL-C changes. Data extraction was performed independently, and conflicts were resolved. Review Manager 5.4 with random effects was employed for statistical analysis, and ROB 2.0 bias evaluation was conducted. The study reported CVD mortality and MACE risk ratios (RRs) with 95% CIs, as well as SBP and LDL-C weighted mean differences (MD). A total of 24 trials were included in this meta-analysis. The results revealed that the polypill was associated with a decreased risk of CVD mortality and major adverse cardiovascular events (MACE). Additionally, a significant reduction in systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C) was observed. This meta-analysis showed that polypill is a viable medication for reducing the risk of CVD mortality and MACE. It is also a beneficial medication for lowering LDL-C levels and SBP.

Exploring the promising application of Be12O12 nanocage for the abatement of paracetamol using DFT simulations.

The removal of paracetamol from water is of prime concern because of its toxic nature in aquatic environment. In the present research, a detailed DFT study is carried out to remove paracetamol drug from water with the help of Be12O12 to eliminate the related issues. Three different geometries (CMP-1, CMP-2, CMP-3,) are obtained with the highest adsorption energies value (Eads) of - 31.2316 kcal/mol for CMP-3 without any prominent structural change. It is observed from the study that O atom from the carbonyl group (C=O) and H atom from O-H group successfully interact with O and Be atoms of the nanocage respectively. Natural bonding orbitals analysis reveals charge transfer to paracetamol drug from Be12O12 nanocage with maximum charge transfer of - 0.159 e for CMP-3 with bond angle of 1.65 Å confirming the stability of the CMP-3 among the optimized complexes. The quantum theory of atoms in molecule concludes that the interaction between paracetamol drug molecule and Be12O12 is purely closed-shell weak electrostatic in nature in CMP-1 and CMP-3 and shared interaction in CMP-2. The thermodynamics analysis witnesses that the process is exothermic and spontaneous. The regeneration study reveals the reversible nature of the adsorbent. The overall study presents Be12O12 nanocage as a potential adsorbent and may be used in future for the purification of water from a number of emerging pollutants.