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.

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.

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, 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.

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.

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.

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.

Structure based virtual screening and molecular simulation study of FDA-approved drugs to inhibit human HDAC6 and VISTA as dual cancer immunotherapy.

Cancer immunotherapy has significantly contributed to the treatment of various types of cancers mainly by targeting immune checkpoint inhibitors (ICI). Among them, V-domain immunoglobulin suppressor of T cell activation (VISTA) has been explored as a promising therapeutic target. Besides, histone deacetylase 6 (HDAC6) has been demonstrated to be efficacious target for several cancers. The current theoretical work was performed to explore the virtual repurposing of the FDA-approved drugs as inhibitors against these two (VISTA and HDAC6) cancers therapeutic targets. The crystal structure of the two proteins were downloaded from PDB and subjected to virtual screening by DrugRep webserver while using FDA-approved drugs library as ligands database. Our study revealed that Oxymorphone and Bexarotene are the top-ranked inhibitors of VISTA and HDAC6, respectively. The docking score of Bexarotene was predicted as - 10 kcal/mol while the docking score of Oxymorphone was predicted as - 6.2 kcal/mol. Furthermore, a total of 100 ns MD simulation revealed that the two drugs Oxymorphone and Bexarotene formed stable complexes with VISTA and HDAC6 drug targets. As compared to the standard drug the two drugs Oxymorphone and Bexarotene revealed great stability during the whole 100 ns MD simulation. The binding free energy calculation further supported the Root Mean Square Deviation (RMSD) result which stated that as compared to the ref/HDAC6 (- 18.0253 ± 2.6218) the binding free energy score of the Bexarotene/HDAC6 was good (- 51.9698 ± 3.1572 kcal/mol). The binding free energy score of Oxymorphone/VISTA and Ref/VISTA were calculated as - 36.8323 ± 3.4565, and - 21.5611 ± 4.8581 respectively. In conclusion, the two drugs deserve further consideration as cancer treatment option.

Molecular docking and in vitro antibacterial activity of chiral phthalimide on ESBL producing gram negative bacteria.

Antibiotic resistance is tricky enemy that challenges our healthcare system. It is a stealthy, adaptive and ever evolving opponent, which can take years to develop but can spread like wildfire. In this study, derivatives of chiral phthalimides were developed with this aim to control the growth of resistant strains of Klebsiella pneumonia, Escherichia coli and Pseudomonas aeruginosa by targeting their resistance causing proteins and explore their binding interaction focal points through computational docking. Total 8 novel chiral phthalimides were synthesized and its antibiogram analysis was done on Muller-Hinton Agar by disc diffusion method. Cytotoxicity studies were made to check efficacy of tested compounds on human RBCs and monitor release of hemoglobin absorbance at 540nm. By using in silico molecular approach, crystal structure of target protein was retrieved from Protein Data Bank and docked through Autodock vina and PyRx. The obtained results revealed that seven out of eight compounds have active inhibitory effects against virulent strains. Minimum Inhibitory Concentration (MIC) was measured for most potent compounds i.e., 2-(1,3-dioxoisoindolin-2-yl)-3-(4-hydroxyphenyl) propanoic acid (compound 7) and 3-(1,3-dioxoisoindolin-2-yl) propanoic acid (compound 8). Docking studies displayed a report of highest affinity binding points i.e., amino acids LYS315, ALA318, TYR150, THR262, HIS314 and ARG148 for compound 7 while ALA 318, LYS 315, ARG14 and ILE291 for compound 8.

Synthesis, Antioxidant, Molecular Docking and DNA Interaction Studies of Metal-Based Imine Derivatives.

Currently, numerous ongoing studies are investigating the interaction of free radicals with biological systems, such as lipids, DNA and protein. In the present work, synthesis, characterization, antioxidant, DNA binding and molecular docking studies of Schiff base ligand and its Ni(II), Co(II), Cu(II) and Zn(II) were evaluated. The metal complexes have shown significant dose-dependent antioxidant activities higher than those of the free ligand but lesser than those of the standard antioxidant, ascorbic acid. The DNA binding constants (Kb) were found in the order Zn(pimp)2 {9.118 × 105 M-1} > H-pimp {3.487 × 105 M-1} > Co(pimp)2 {3.090 × 105 M-1} > Ni(pimp)2 {1.858 × 105 M-1} > Cu(pimp)2 {1.367 × 105 M-1}. Binding constants (Kb) values calculated from the molecular docking analysis were found to be in close agreement with the experimental results. The obtained results indicate the importance of synthesis complexes as a source of synthetic antioxidants and anticancer drugs.

Novel flurbiprofen clubbed oxadiazole derivatives as potential urease inhibitors and their molecular docking study.

In this study, twenty eight novel oxadiazole derivatives (5-32) of the marketed available non-steroidal anti-inflammatory drug (NSAID), (S)-flurbiprofen (1), were synthesized via I2 mediated cyclo-addition reaction in better yields. The synthesized hydrazone-Schiff bases were cyclized with iodine by using potassium hydroxide as a base in DMSO solvent to obtain oxadiazole derivatives (5-32). Structures of the synthesized products were confirmed with HR-ESI-MS, 1H-NMR spectroscopy and CHN analysis. After structure confirmations all analogs were evaluated for urease (in vitro) inhibitory activity. Amongst the series, fourteen compounds 20, 26, 30, 24, 21, 16, 28, 31, 32, 7, 19, 13, 10, and 6 were found to be excellent inhibitors of urease enzyme, having IC50 values of 12 ± 0.9 to 20 ± 0.5 µM, better than the standard thiourea (IC50 = 22 ± 2.2 µM), whereas the remaining fourteen derivatives displayed good to moderate activity. The in silico study was executed to analyse the interaction between the active site of the enzyme (urease) and the produced compounds. The docking study revealed that compounds 20, 26, 30, 24, 21, 16, 28, 31, 32, 7, 19, 13, 10, and 6 had lower docking scores than the standard compound thiourea and revealed better interactions with the urease enzyme.

In vitro evaluation of herbal based Lesh Nat B cream against Leishmania tropica.

Pentavalent antimonials continue to be the standard treatment for cutaneous leishmaniasis. But their use is retarded owing to highly-priced, prolonged hospitalization, noxious and poor solubility. Therefore, there is a dire need to characterize new potential compounds possessing anti-leishmanial activity. Topical therapies that are more successful are an essential alternative therapeutic option for the localized self-limiting form of this disease. We tested the herbal-based topical cream Lesh Nat B against Leishmania tropica KWH23 promastigotes and axenic amastigotes in vitro. The anti-leishmanial activity of Lesh Nat B cream was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay against promastigotes and axenic amastigotes. The results of Lesh Nat B cream were concentration and incubation time-dependent. After 72 h of incubation, Lesh Nat B cream efficiently suppresses the promastigote form of the parasite, followed by 48 h and 24 h. At 72 h, the lowest and highest levels of activity were 37% and 90%. Amastigotes had a minimum activity of 34% and a maximum activity of 78.5%, respectively. This formulation was more cytotoxic against promastigote form than amastigotes form at 72 h incubation periods. All the experiments were carried out in triplicates. Half-maximal inhibitory concentration (IC50) values were determined to be (66 ug/ml) and (70 ug/ml) against promastigote and amastigote forms, respectively. Moreover, 1.63% hemolytic activity was observed in Lesh Nat B cream at (10 µg/ml) while 3% hemolytic activity was observed at (37 µg/ml). It can be concluded that Lesh Nat B cream demonstrated effective Leishmanicidal and less hemolytic activity and can be used as an alternative therapeutic option for the treatment of cutaneous leishmaniasis; however, more studies are expected to justify its effectiveness in treating cutaneous leishmaniasis in both humans and animals.

Novel Schiff bases of Vanillin: potent inhibitors of macrophage harbored Leishmania tropica.

Due to limited chemotherapeutic options for leishmaniasis, novel synthetic compounds are gaining attention for evaluation against leishmaniasis. This study aimed to synthesize the compound's Schiff bases of Vanillin to investigate and evaluate their anti-leishmanial potentials against intracellular protozoan parasites Leishmania tropica. In the current study, the phenomena of synergism by designing Schiff bases with Vanillin enhances their desired importance. A total of five compounds Schiff bases of Vanillin were synthesized using different aromatic amines and Vanillin. The structural analysis of all the compounds was done through FT-IR (Fourier Transformer-Infrared), thin layer chromatography, and spectroscopic techniques such as 13C-NMR, mass spectrometry, and 1H-NMR. The antimicrobial properties of all the compounds ZI-1, ZI-2, BS-1, KH-1, and FA-2 against promastigotes and amastigotes forms of L. tropica were analyzed at three different concentrations 25, 50, and 100 µg/ml. The in-vitro MTT assay was performed to calculate the percent inhibition, IC50 values, and their cytotoxicity. The highest percent inhibition values against promastigote form of L. tropica were BS-1 53.78% at 25 µg/ml, ZI-2 66.95% at 50 µg/ml, and again ZI-2 76.92% at 100 µg/ml. Similarly, the highest percent inhibition values against intracellular amastigote stage were BS-1 55.77% at 25 µg/ml, ZI-2 67.78% at 50 µg/ml and again ZI-2 84.93% 100 µg/ml. The highest potency was recorded for BS-1 in both stages, with IC50 values of 9.83 and 4.27 µg/ml against promastigotes and intracellular amastigotes, respectively. The percent hemolysis as toxicity; the lowest percent hemolysis was recorded for ZI-1 at three different concentrations of 25, 50, 100 µg/ml of 2.60, 3.50, and 6.31, respectively. These results suggested that all the compounds exhibited anti-leishmanial activity, with BS-1 as the most potent. Further studies are suggested to increase the activity of compounds with structural modifications by the addition of some other synergistic, novel, and analogue compounds.

Synthesis, molecular structure and urease inhibitory activity of novel bis-Schiff bases of benzyl phenyl ketone: A combined theoretical and experimental approach.

Background: Urease belongs to the family of amid hydrolases with two nickel atoms in their core structure. On the basis of literature survey, this research work is mainly focused on the study of bis-Schiff base derivatives of benzyl phenyl ketone nucleus. Objective: Synthesis of benzyl phenyl ketone based bis-Schiff bases in search of potent urease inhibitors. Method: In the current work, bis-Schiff bases were synthesized through two steps reaction by reacting benzyl phenyl ketone with excess of hydrazine hydrate in ethanol solvent in the first step to get the desired hydrazone. In last, different substituted aromatic aldehydes were refluxed in catalytic amount of acetic acid with the desired hydrazone to obtain bis-Schiff base derivatives in tremendous yields. Using various spectroscopic techniques including FTIR, HR-ESI-MS, and 1H NMR spectroscopy were used to clarify the structures of the created bis-Schiff base derivatives. Results: The prepared compounds were finally screened for their in-vitro urease inhibition activity. All the synthesized derivatives (3-9) showed excellent to less inhibitory activity when compared with standard thiourea (IC50 = 21.15 ± 0.32 µM). Compounds 3 (IC50 = 22.21 ± 0.42 µM), 4 (IC50 = 26.11 ± 0.22 µM) and 6 (IC50 = 28.11 ± 0.22 µM) were found the most active urease inhibitors near to standard thiourea among the synthesized series. Similarly, compound 5 having IC50 value of 34.32 ± 0.65 µM showed significant inhibitory activity against urease enzyme. Furthermore, three compounds 7, 8, and 9 exhibited less activity with IC50 values of 45.91 ± 0.14, 47.91 ± 0.14, and 48.33 ± 0.72 µM respectively. DFT used to calculate frontier molecular orbitals including; HOMO and LUMO to indicate the charge transfer from molecule to biological transfer, and MEP map to indicate the chemically reactive zone suitable for drug action. The electron localization function (ELF), non-bonding orbitals, AIM charges are also calculated. The docking study contributed to the analysis of urease protein binding.