Potential of Tryptamine Derivatives as Multi-Target Directed Ligands for Alzheimer's Disease: AChE, MAO-B, and COX-2 as Molecular Targets.

Extensive research has been dedicated to develop compounds that can target multiple aspects of Alzheimer's disease (AD) treatment due to a growing understanding of AD's complex multifaceted nature and various interconnected pathological pathways. In the present study, a series of biological assays were performed to evaluate the potential of the tryptamine analogues synthesized earlier in our lab as multi-target-directed ligands (MTDLs) for AD. To assess the inhibitory effects of the compounds, various in vitro assays were employed. Three compounds, SR42, SR25, and SR10, displayed significant AChE inhibitory activity, with IC50 values of 0.70 µM, 0.17 µM, and 1.00 µM, respectively. These values superseded the standard drug donepezil (1.96 µM). In the MAO-B inhibition assay, SR42 (IC50 = 43.21 µM) demonstrated superior inhibitory effects as compared to tryptamine and other derivatives. Moreover, SR22 (84.08%), SR24 (79.30%), and SR42 (75.16%) exhibited notable percent inhibition against the COX-2 enzyme at a tested concentration of 100 µM. To gain insights into their binding mode and to validate the biological results, molecular docking studies were conducted. Overall, the results suggest that SR42, a 4,5 nitro-benzoyl derivative of tryptamine, exhibited significant potential as a MTDL and warrants further investigation for the development of anti-Alzheimer agents.

Revealing analgesic and anxiolytic potentials of synthetic benzimidazole analogues: An in-vivo and in-silico study.

Certain drugs have potential to affect and alter individual's behavior. On the other hand, pain is a complex phenomenon with various treatment options; analgesic medicines are the primary source. Therefore, this study was based on examining some of the benzimidazole analogues for their analgesic as well as behavioral potential following Tail immersion test and Open field test respectively. In addition, molecular docking was performed to find the interaction of these compounds with the active site using AutoDock Vina which was further visualized through Discovery Studio Visualizer. It was seen that the cyano-methyl benzimidazole derivatives (CMB1-CMB3) showed relief in pain as compared to benzimidazole derivatives (BI1-BI3), CMB2 demonstrated highly potent analgesic effect. Likewise, all structures except BI1 displayed increase locomotion during open field test and can be offered as anxiolytic compounds. Almost all derivatives showed improve binding energies for the tested proteins where the high analgesic action of CMB2 might be correlated to its high binding affinity and interaction at µOR. It was also noticed that all structures except BI showed possible binding interaction with GABAA receptor and hence possessed anxiolytic like potential. Thus, this study offered benzimidazole analogues for further drug development of analgesic and anxiolytic like compounds.

Green synthesized silver nanoparticles from eucalyptus leaves can enhance shelf life of banana without penetrating in pulp.

Bananas are exposed to serious post-harvest problems resulting in agricultural and economic losses across the world. The severity of problem is linked with the process of rapid ripening and pathogens attack. Such problems have led to economic losses as well as a lower yield of nutritionally rich bananas. The global demand to increase the life span of bananas and their protection from pathogens-borne diseases urged the use of antimicrobial edible coatings of nanoparticles. The present experiment has explored the innovative development of green synthesized nanoparticles from Eucalyptus leaf extract (ELE) to increase the shelf life of bananas up to 32 days from the day of collection. Statistically significant results were recorded (P = 0.05) by applying five different concentrations of silver nanoparticles (AgNPs) in ranges of 0.01-0.05%. Various morphological and physiological parameters such as color, decay, firmness, weight loss, pulp to peel ratio, pH, titrable acidity (TA), phenolic contents, protein estimation, ethylene production, starch content and total soluble sugars were measured in Cavendish banana (Basrai). Bananas treated with 0.01% AgNPs showed maximum control on its ripeness over morphological and physiological changes. The increase in shelf life was in order 0.01%>0.02%>0.03%>0.04%>0.05%> control. Further, AgNPs reduced the process of ripening by controlling ethylene production. The result has also proved the safety of banana consumption by simple removal of banana peel as penetration of AgNPs from the peel to the pulp was not detected. It is recommended to use 0.01% AgNPs to enhance the shelf life of banana without effecting its nutritive value.

Studies on Synthesis, Characterization, and Photocatalytic Activity of TiO2 and Cr-Doped TiO2 for the Degradation of p-Chlorophenol.

TiO2 and Cr-TiO2 nanoparticles (NPs) have been synthesized by the sol-gel method using titanium isopropoxide as the precursor of Titania. The prepared samples were analyzed by employing scanning electron microscopy, energy-dispersive X-ray spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy, and Fourier transform infrared analyses. Under UV irradiation, the photocatalytic activities of TiO2 and Cr-TiO2 were observed by estimating the % degradation of p-chlorophenol (PCP) as a sample pollutant. The extent of degradation was investigated, varying the catalyst dosage, initial PCP concentration, irradiation time, and solution pH. The experimental results show that efficiency of catalysts initially increases but decreases later on, whereas the % degradation of PCP is the highest at its lowest initial concentration. For TiO2 and Cr-TiO2 NPs at their optimal catalyst dosage of 2.0 g/L, acidic pH, and with UV irradiation for 90 min, the observed % degradation of PCP is 50.23 ± 3.12 and 66.51 ± 2.14%, respectively. Thus, the prepared Cr-TiO2 NPs have enhanced the degradation efficiency of PCP with an irradiation time which is four time less than those reported earlier. From the kinetics analysis, the degradation reaction of PCP is found to follow a pseudo-first-order model and the rate constants are 0.0075 and 0.0122 min-1 for pure TiO2 and Cr-TiO2 NPs, respectively. The present study has further revealed that owing to the lower rate of electron-hole pair recombination, the photocatalytic activity of Cr-TiO2 NPs becomes higher than that of TiO2. Therefore, as viable photocatalytic agents, Cr-TiO2 NPs are suggested to be used also for efficient degradation of other organic pollutants.

Production of Glucoamylase from Novel Strain of Alternaria Alternata under Solid State Fermentation.

Glucoamylase has an essential role as biocatalyst in various important industries of Pakistan. It is synthesized by using various fungal and bacterial strains, and different ecocultural conditions are applied under solid substrate fermentation method (SSF) to get the highest yield of glucoamylase. Alternaria alternata is an important fungus that can grow on industrial raw material like wheat bran, dried potato powder, tea leaves, rice husk, and sugar cane peel which are used as substrate. Among all, dried potato powder (10g) proved the best fermentation media for growth of fungal strain as well as maximum glucoamylase producer. Moreover, several chemical and physical states were also explored through solid substrate fermentation technique on glucoamylase yield. The highest glucoamylase production was recorded after 72 hours incubation in incubation chamber with 10g raw substrate, 1ml inoculum spore solution, 30°C temperature, and 5 pH. Further, phosphate buffer (5 pH) as moistening agent, 5% starch concentration and media additive as nitrogen (yeast extract), and carbon source (maltose) were screened for maximum glucoamylase titer (17.3 ± 0.05a°U/ml/min) and the highest specific activity (39.2U/mg). These cultural conditions were most appropriate for growth of A. alternata on solid media and production of highest glucoamylase under solid state fermentation procedure that could be utilized for commercial synthesis of glucoamylase.

Predictors of entrepreneurial intentions: The role of prior business experience, opportunity recognition, and entrepreneurial education.

Entrepreneurship and its influence on the development of the economy are significant in competitive global advancement. Entrepreneurs need entrepreneurial intentions to improve the commercial environment of the country. Therefore, studying entrepreneurial intentions' influencing predictors is vital for business development. We collected data from small and medium-sized enterprises (SMEs) employees of the developing country and used partial least square structured equation modeling to analyze the proposed relationships. The results assist the literature extension and practically contribute to developing entrepreneurs' intentions through education and opportunity recognition. The findings aid the institutions in improving course planning and establishing practical business setups. This study facilitates the government's ideas of commencing entrepreneurial businesses through proper resource provisions for the entrepreneurs.

Determination of ionization constant and drug-likeness prediction of synthetic isoniazid derivatives.

Determination of ionization constant, commonly termed pKa is of prime interest in a wide range of pharmaceutical Research fields. The pKa of a compound is critical as it influences on its physicochemical parameters in biological and environmental systems. The study of pKa is also essential not only for the formulation of drugs and optimization of a variety of novel analytical methods, establishing new pharmaceutical dosage forms yet the exploration of the mechanism of action of drugs. In this research work, we have determined pKa values of isoniazid (INH) derivatives; N'-[(4-methyl benzoyl)] pyridine-4-carbohydrazide (I) and [2-oxo-2-(4-phenyl phenyl) ethyl] (pyridine-4-yl formamido) azanium bromide (II) through UV- spectrophotometry, a method is known for the accuracy and precision of results. These two compounds (I and II) were synthetically prepared in our lab by derivatizing INH and reported by Naeem et al in the year 2014. The mean pKa values for compounds I and II were experimentally determined as 7.37 and 3.76 respectively. The study is helpful in understanding the physicochemical behavior of these compounds in a biological system. Different pharmacokinetic parameters were also predicted using online web tools which ensured significant drug-likeness for both compounds.

New series of hydrazinyl thiazole derivatives of piperidin-4-one: Synthesis, structural elucidation, analgesic activity and comparative structure activity relationship.

Seven new hydrazinyl thiazole derivatives of piperidin-4-one (PE3-PE9) have been synthesized by cyclization of intermediate thiosemicarbazone derivative (PE2). Parent molecule (PE1) was synthesized by one pot total synthesis using Mannich condensation reaction. Percent yield of most of the compounds found in between 70-85%. Compounds were identified by spectroscopic analysis. In vivo analgesic activity was examined using tail flick method. One-way ANOVA was used to compare the mean latency time of synthesized derivatives with control and standard. Analgesic activity was discussed in terms of structural differences between compounds. Among allthe derivatives thiosemicarbazone derivative showed good analgesic activity (195.24%). Methoxy (-OCH3) and bromo (-Br) containing thiazole derivative also showed good pain reducing property (167.62%, 203%) at a dose of 30mg/kg.

1,3-di-4-piperidylpropane derivatives as potential acetyl cholinesterase antagonists: Molecular docking, synthesis, and biological evaluation.

Acetylcholine esterase (AChE) is a key biological target responsible for the management of cholinergic transmission, and its inhibitors are used for the therapy of Alzheimer's disease. In the present study, a small library of molecules with 1,3-di-4-piperidylpropane nucleus were docked on AChE. The selected compounds were synthesized and evaluated for their enzyme inhibition. P25 and P17 expressed significantly higher AChE inhibition than standards with IC50 values of 0.591µM and 0.625µM, respectively. Binding mode of derivatives in the active site of AChE revealed dual binding of molecules in peripheral anionic site (PAS) and catalytic anionic site (CAS) of enzyme cavity.

Impact of supervisory behavior on sustainable employee performance: Mediation of conflict management strategies using PLS-SEM.

This study investigates the relationship between supervisory behavior, conflict management strategies, and sustainable employee performance and inquires the mediating effect of conflict management strategies. Data were collected from the SMEs of the manufacturing industry of Pakistan. The significance of the model was assessed using the PLS-SEM (structural equation modeling). The findings of the study revealed a positive and significant relationship between supervisory behavior and sustainable employee behavior. Similarly, conflict management strategies had a positive effect on the relationship between supervisory behavior and sustainable employee behavior. This study adds in the current literature of supervisory behavior as a critical predictor of sustainable employee performance in two ways. Firstly, this study validates Conflict management strategies as an influential mediator between the relationship of supervisory behavior and sustainable employee performance. Secondly, this study provides substantial practical implications for managers at SMEs to enhance sustainable employee performance through supervisory behavior, stimulated by conflict management strategies. This study is based on cross-sectional data; more longitudinal studies can further strengthen the generalizability of relationships between the constructs. The study adds in the current literature of PLS-SEM as an assessment model for direct and mediation relationships.

Moxifloxacin induced encephalopathy in disseminated tuberculosis: A case report.

Moxifloxacin is a third-generation fluoroquinolone antibiotic with broad spectrum activity and also used as component of anti-tubercular therapy (ATT). Though frequently prescribed, moxifloxacin induced encephalopathy is uncommonly seen. Here we describe a forty four year old male, with features of disseminated tuberculosis (TB) and suspected case of multi-drug resistance (MDR), who developed acute encephalopathy. Extensive laboratory investigations, neuroimaging of brain, cerebrospinal fluid analysis was unremarkable. On stopping moxifloxacin, which was being administerd as part of ATT for MDR TB, encephalopathy resolved completely, thereby proving it to be a case of moxifloxacin induced encephalopathy. To conclude, by presenting this case, we wish to raise awareness about moxifloxacin induced encephalopathy among healthcare providers.

Molecular docking, synthesis and biological evaluation of phenacyl derivatives of 9-aminoacridine as anti-Alzheimer's agent.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder mainly characterized by progressive deterioration of memory and impaired cognitive function. The most promising approach for symptomatic relief of AD is to inhibit acetylcholinesterase (AChE). On the basis of this approach in-house library of 9-aminoacridine derivatives were constructed and allowed to docked against human acetylcholinesterase (hAChE) (PDB ID: 4EY7), using MOE 2018.01 and PyRx 0.9.2 (AutoDock Vina). Top ranked and best fitted molecules were synthesized by targeting the 9-amino group of aminoacridine with substituted phenacyl halides. Anti-Alzheimer's potential was checked by in vitro AChE inhibition, antioxidant activity (DPPH scavenging ability) and fibril disaggregation. Subjected ligands suggested as promising multitargeted candidate with pronounced results in term of IC50 values (AChE inhibition 2.400-26.138µM), however, none of them showed potential towards fibril inhibition.

In-silico determination of pKa and logp values of some isoniazid synthetic analogues using Marvin software.

Among the physicochemical properties, pKa and LogP values help us in studying drug parameters like ADME and could be predicted to some extent. With this view, here we wish to predict these two properties of our previously synthesized biologically active derivatives of isoniazid using on-line available program Marvin, a Java-based chemical software application frequently used for chemical modeling. According to Marvin, pKa values predicted 99.99% unionized states of INH and some derivatives at physiological pH 7.4. Marvin calculated LogP values estimated good oral absorption for all the synthesized compounds. Therefore it can be said that the findings of the study emerged in an ideal region that permits the formulation of these derivatives. Since this was just a theoretical study, it demands more experimentation to determine accurate situation.

The Impact of Transformational Leadership on Employee Retention: Mediation and Moderation Through Organizational Citizenship Behavior and Communication.

This study investigates the impact of transformational leadership on employee retention in small- and medium-sized enterprises (SMEs) and probes the mediating role of organizational citizenship behavior (OCB) and the moderating role of communication. Data were collected using convenience sampling from 505 employees of SMEs. A Smart PLS structural equation modeling (PLS-SEM) was used to estimate the various relationships. The findings of the study reveal a positive and significant relationship between transformational leadership and OCB. Similarly, this study finds a positive and significant relationship in OCB and employee retention. In addition, OCB had a positive mediating effect on the relationship between transformational leadership and employee retention. Furthermore, communication positively moderates the transformational leadership- OCB and OCB-employee retention relationships. Leaders at SMEs should implement the traits of transformational leadership such as developing a compelling vision for employees, focusing on goal achievement, having problem-solving techniques, having a sense of purpose, and spending time on the training and development of the team to enhance OCB and employee retention.

Antimicrobial activity of Mycobacteriophage D29 Lysin B during Mycobacterium ulcerans infection.

Buruli Ulcer (BU) is a cutaneous disease caused by Mycobacterium ulcerans. The pathogenesis of this disease is closely related to the secretion of the toxin mycolactone that induces extensive destruction of the skin and soft tissues. Currently, there are no effective measures to prevent the disease and, despite availability of antibiotherapy and surgical treatments, these therapeutic options are often associated with severe side effects. Therefore, it is important to develop alternative strategies for the treatment of BU. Endolysins (lysins) are phage encoded enzymes that degrade peptidoglycan of bacterial cell walls. Over the past years, lysins have been emerging as alternative antimicrobial agents against bacterial infections. However, mycobacteria have an unusual outer membrane composed of mycolylarabinogalactan-peptidoglycan. To overcome this complex barrier, some mycobacteriophages encode a lipolytic enzyme, Lysin B (LysB). In this study, we demonstrate for the first time that recombinant LysB displays lytic activity against M. ulcerans isolates. Moreover, using a mouse model of M. ulcerans footpad infection, we show that subcutaneous treatment with LysB prevented further bacterial proliferation, associated with IFN-γ and TNF production in the draining lymph node. These findings highlight the potential use of lysins as a novel therapeutic approach against this neglected tropical disease.

Synthesis, characterization and SAR of novel Bezimidazole derivatives as Nematicidal agents.

Six novel analogues were prepared by reacting benzimidazole molecules (BM and CMB) propiophenone and benzoyl chlorides respectively. The structures of newly synthesized compounds were determined with the help of spectroscopic techniques. The compounds were subjected to in-vitro screening for their activity against nematodes. It was observed that the benzimidazole (BM) derivatives possessed more nematicidal activity as compared to that of cyanomethyl-benzimidazole (CMB) for Meloidogyne incognita. Among them, the propiophenone substituted benzimidazole derivative B3 was found to be the most active compound and can be further studied as lead molecule for development of anthelmintic drugs.

Pharmacophoric screening of newly synthesized isoniazid derivatives and their antimycobacterial activity.

Mycobacterium tuberculosis is clinically recognized as a causative agent of Tuberculosis. Keeping in view, this study was endeavored to screen our previously synthesized seventeen INH analogues for their antimycobacterial potential using proportion method. During this process, INH and all the seventeen compounds were examined at different concentrations of 0.05, 0.1 and 0.2µg/mL which were prepared using Lowenstein-Jensen (LJ) base. For drug susceptibility test, three Mycobacterial strains ATCC H37Rv, known INH-sensitive and INH-resistant strains were selected, sub-cultured on LJ Medium and serial diluted to achieve 1:10, 1:100, 1:1000 and 1:10000 from calibrated bacterial suspension Mcfarland No. 1. Dilutions of 1:100 and 1:10000 were added to drug free medium and 1:100 bacterial suspension was added to each of the test concentrations and finally incubated for 4-6 weeks at 37°C. It was observed that only compounds II and XI were active against MTb. Compounds III, IX and X also showed activity but were less potent. Ligand Scout 3.02[il_10] was used to perform pharmacophore-based screening where important pharmacophoric features were identified in the structures of these compounds which could be related to their observed antimycobacterial activity.

Cytotoxic and acute toxicity studies of isoniazid derivatives.

Cancer is ultimately the result of cells that hysterically grow and do not die. Cells can experience uncontrolled growth if there are mutations to DNA, and therefore, alterations to the genes involved in cell division. Cancer occurs when a cell's gene mutations make the cell unable to correct DNA damage and is unable to destroy itself. There are over 100 different types of cancer each classified by the type of initially affected cell. Isoniazid, a well-known antitubercular agent has been reported to exhibit some cytotoxic activity. This finding prompt us to carry out this study where isoniazid and its sixteen derivatives were studied for any possible cytotoxic activity against Human astrocytoma SNB-19 cells, human Dukes' type C colorectal adenocarcinoma HCT-15 cells, human Dukes' type D colorectal adenocarcinoma COLO-205 cells, and human prostate adenocarcinoma (grade IV) PC-3 cells. Among the test compounds, SN-07 (a phenacyl derivative with para phenyl substitution) demonstrated slight cytotoxic effects on two types of human colorectal adenocarcinoma cells HCT-15 and COLO-205. Moreover, the acute toxicity of the compounds was also estimated in which some compounds were evaluated with more LD50 values than isoniazid.

MeCP2_E1 N-terminal modifications affect its degradation rate and are disrupted by the Ala2Val Rett mutation.

Methyl CpG-binding protein 2 (MeCP2), the mutated protein in Rett syndrome (RTT), is a crucial chromatin-modifying and gene-regulatory protein that has two main isoforms (MeCP2_E1 and MeCP2_ E2) due to the alternative splicing and switching between translation start codons in exons one and two. Functionally, these two isoforms appear to be virtually identical; however, evidence suggests that only MeCP2_E1 is relevant to RTT, including a single RTT missense mutation in exon 1, Ala2Val. Here, we show that N-terminal co- and post-translational modifications differ for MeCP2_E1 and MeCP2_E1-Ala2Val, which result in different protein degradation rates in vitro. We report complete N-methionine excision (NME) for MeCP2_E1 and evidence of excision of multiple alanine residues from the N-terminal polyalanine stretch. For MeCP2_E1-Ala2Val, we observed only partial NME and N-acetylation (NA) of either methionine or valine. The localization of MeCP2_E1 and co-localization with chromatin appear to be unaffected by the Ala2Val mutation. However, a higher proteasomal degradation rate was observed for MeCP2_E1-Ala2Val compared with that for wild type MeCP2_E1. Thus, the etiopathology of Ala2Val is likely due to a reduced bio-availability of MeCP2 because of the faster degradation rate of the unmodified defective protein. Our data on the effects of the Ala2Val mutation on N-terminal modifications of MeCP2 may be applicable to Ala2Val mutations in other disease genes for which no etiopathological mechanism has been established.

Pattern recognition receptors and coordinated cellular pathways involved in tuberculosis immunopathogenesis: Emerging concepts and perspectives.

Pattern Recognition Receptors (PRRs) play a central role in the recognition of numerous pathogens, including Mycobacterium tuberculosis, resulting in activation of innate and adaptive immune responses. Besides Toll Like Receptors, C-type Lectin Receptors and Nod Like Receptors are now being recognized for their involvement in inducing immune response against M. tuberculosis infection. Although, a functional redundancy of the PRRs has also been reported in many studies, emerging evidences support the notion that a cooperative and coordinated response generated by these receptors is critical to sustain the full immune control of M. tuberculosis infection. Many of the PRRs are now found to be involved in various cellular host defenses, such as inflammasome activation, phagosome biogenesis, endosomal trafficking, and antigen processing pathways that are all very critical for an effective immune response against M. tuberculosis. In support, polymorphism in several of these receptors has also been found associated with increased susceptibility to tuberculosis in humans. Nonetheless, increasing evidences also show that in order to enhance its intracellular survival, M. tuberculosis has also evolved multiple strategies to subvert and reprogram PPR-mediated immune responses. In light of these findings, this review analyzes the interaction of bacterial and host factors at the intersections of PRR signaling pathways that could provide integrative insights for the development of better vaccines and therapeutics for tuberculosis.