GI Absorption Research Articles

A Schiff Base with Polymorphic Structure (Z′ = 2): Investigations with Computational Techniques and in Silico Predictions

In this study, we report a newly synthesized Schiff base molecule named (E)-N-(2-chloropyridin-3-yl)-1-(5-nitro-2-(piperidin-1-yl)phenyl)methanimine. We also report its structural, chemical, surface, and electronic properties, potential targets, drug-likeness, ADME and toxicity profile, and docking studies for the main protease (Mpro) of SARS-CoV-2. The scope of this study includes the topological and electronic properties, intermolecular interactions, physicochemical and pharmacokinetic properties, metabolic pathways, toxicity endpoints, blood–brain barrier (BBB) permeability, and intestinal absorption activities. We performed the above analyses using bioinformatics/chemoinformatics tools and computational techniques. The topic crystal/compound (TC) contains two crystallographically independent molecules in the asymmetric unit (Z′ = 2). TC is open to attack by electrophilic and nucleophilic species and is a soft, chemically reactive, kinetically unstable material. There are no deviations from the known drug-likeness rules. BBB penetration and GI absorption of TC are possible. The docking values of the complex Mpro/TC and Mpro/native ligand N3 were calculated to be −8.10 and −7.11 kcal/mol, respectively. Therefore, we can say that TC is a potential Mpro inhibitor and can be investigated for further laboratory studies.

Bioevaluation, Pharmacokinetics and Molecular docking study of Phenylpropanoid rich rhizome essential oil of understudied Zingiber neesanum from Konkan region of India

Zingiber neesanum a species from the Zingiberaceae family exhibits convincing medicinal applications and is available vastly in the Konkan region. Its anti-inflammatory potential is an unexplored part. This work presents a Bioevaluation, Pharmacokinetics and Molecular docking study emphasizing the anti-inflammatory potential of rhizome oil of this species. An ultrasound-assisted solvent extraction method was employed to isolate oil and characterized by GC/FID and GC/HRMS techniques. The antimicrobial efficacies were checked by the Broth and Agar dilution protocols while the DPPH and ABTS assays were employed to test antioxidant potency. The anti-inflammatory potentials were tested by 3 methods-Heat-induced hemolysis, Inhibition of albumin denaturation and Proteinase inhibitory action. ADMET study was performed by the Swiss-ADME server while the docking was performed with AutoDock 4.2 software with a major component, [E]-3,4-Dimethoxy cinnamic acid methyl ester ([E]-3,4-DCME) using trypsin receptor. A pale yellow-colored essential oil was dominated by Phenylpropanoids (62.09%). Excellent antimicrobial potentials were observed versus Staphylococcus aureus and Candida albicans while excellent antioxidant activities were observed in both assays. But best anti-inflammatory action was documented in the albumin denaturation method. The pharmacokinetic properties of [E]-3,4-DCME, like high GI absorption, zero Lipinski violation with good bioavailability score etc., were promising. The docking results revealed that [E]-3,4-DCME has substantial binding affinity due to ‘H’ bonding interactions, and non-bonded Van der Waals and ?-alkyl type interactions with the active site residues of a receptor. So, this study concludes that the rhizome oil of this underexplored species could be utilized in developing novel phytopharmaceuticals after further study.

Synthesis of Amide Derivatives as Tubulin Polymerization Inhibiting Antiproliferative Agents

AbstractHerein, we synthesized some new imidazole‐tetrazole‐amide hybrids (7 a–o) and investigated their antiproliferative activity on three human cancer cell lines like HEPG2, A549 and MCF‐7. Generally, most of them displayed more activity on A549 than other two cell lines. Specifically, compounds N‐(3,5‐dimethoxyphenyl)‐2‐(5‐(1‐methyl‐1H‐imidazol‐2‐yl)‐2H‐tetrazol‐2‐yl)acetamide (7 b) and N‐(4‐chloro‐3,5‐dimethoxyphenyl)‐2‐(5‐(1‐methyl‐1H‐imidazol‐2‐yl)‐2H‐tetrazol‐2‐yl)acetamide (7 m) had almost similar potency on A549, while, they had significant activity on MCF‐7 in comparison to the standard drug Combretastatin A‐4 (CA‐4). Besides, compounds 4‐(2‐(5‐(1‐methyl‐1H‐imidazol‐2‐yl)‐2H‐tetrazol‐2‐yl)acetyl)benzonitrile (7 j) and N‐(3,5‐dichlorophenyl)‐2‐(5‐(1‐methyl‐1H‐imidazol‐2‐yl)‐2H‐tetrazol‐2‐yl)acetamide (7 k) showed most promising activity against A549 as compared to the CA‐4. The uppermost activity against A549 found for the compounds 7 j and 7 m have IC50 values 1.09 and 1.26 μM respectively. The ability of potent compounds 7 b, 7 j, 7 k and 7 m to inhibit the tubulin polymerization was then studied and found that compounds 7 b and 7 m exhibited promising potency in comparison to the CA‐4. Further, molecular docking studies of compounds 7 b, 7 j, 7 k and 7 m into the tubulin's colchicine‐binding site revealed the possible interactions with tubulin. Finally, in silico ADMET studies revealed that compounds 7 b, 7 j, 7 k and 7 m showed high GI absorption and followed rules of Lipinski, Ghose, Veber, Egan and Muegge without any deviation. Further anticancer mechanism studies are under progress.

Design, synthesis and in silico evaluation of newer 1,4-dihydropyridine based amlodipine bio-isosteres as promising antihypertensive agents.

Hypertension remains a major global health concern, prompting ongoing research into innovative therapeutic approaches. This research encompasses the strategic design, synthesis, and computational assessment of a novel series of 1,4-dihydropyridine based scaffolds with the objective of developing promising antihypertensive agents as viable alternatives to the well-established dihydropyridine based drugs such as amlodipine, felodipine, nicardipine, etc. The crystal structure of the lead compound determined using X-ray crystallography offers crucial insights into its 3D-conformation and intermolecular interactions. In silico molecular docking experiments conducted against the calcium channel responsible for blood pressure regulation revealed superior docking scores for all the bioisosteres P1-P14 than the standard amlodipine, indicating their potential for enhanced therapeutic efficacy. Extensive ADMET profiling and structure-activity relationship (SAR) elucidated favourable pharmacokinetic properties and essential structural modifications influencing antihypertensive effectiveness. Specifically, P6-P10, P12 and P14 hybrids were found in accordance with Lipinski rules and exhibited druglikeliness attributes, involving high GI absorption and no BBB permeance. In particular, P7 was found to be crystalline in nature having the highest binding affinity with the concerned calcium channels with excellent ADMET profile. The findings highlight the significance of the presence of triazole tethered aryl/heteroaryl ring in the synthesized hybrids, providing a foundation for further preclinical and clinical translation as antihypertensive medications.

An in silico study of bioactive compounds of Annona muricata in the design of ani-prostate cancer agent: MM/GBSA, pharmacophore modeling and ADMET parameters

One of the most frequent diseases that affect and kill men globally is prostate cancer. Treatment for prostate cancer has become unpleasant and upsetting for individuals due to the resulting resistance, toxicity, and adverse effects of standard chemotherapies. Consequently, we report the identification of 263 bioactive chemicals in this investigation, some of which are responsible for known anti-cancer effect from Annona muricata using molecular docking, binding free energy estimates, induced-fit docking, gene enrichment analysis, molecular dynamic simulations, and ADMET predictions as examples of in silico approaches. The top 8 scoring compounds from a screening of 263 A. muricata samples revealed varying binding affinities between −9.854 and −8.179 kcal/mol towards the Human steroid 5′-reductase 2 enzyme. Amidst the top eight scoring compounds, annopentocin A, muricatetrocin A, and annohexocin had docking scores of −9.854, −9.337, and −9.337, respectively. The compounds such as annopentocin A communicated with amino acids of medical relevance such as GLU 57, ARG 227, TYR 91, TYR 98, LEU 111, SER 31 via H-bond and TRP 53, PHE 194, 118, 223, 219, 216, LEU 20, 17, 125, 224, 111, 167, ALA 117, TYR 33, 91, 98, 107, CYS 119, ILE 112 via Hydrophobic interaction. The compounds' capacity to impede protein activity was additionally confirmed by preferable docking scores in the induced-fit docking. Annopentocin A, Muricatetrocin A, Isoannonacinone, Annomuricin A and Muricatin C obeyed Lipinski's rule of 5 with favourable toxicity as well as pharmacokinetic prediction. However, there tend to be poor solubility profile and low GI absorption by the compounds which makes them more suitable for intravenous and topical administration than oral administration for optimal efficacy.

ADMET-Evaluation, Pharmacokinetics, Drug-likeness and Medicinal Chemistry of GCMS Identified Bioactive Compounds of Moringa oleifera Natural-Ripened-Dried Methanolic Pod Extract (MOMPE) as a Potential Source of Natural Drug Frontrunner for Next Generation

Over centuries, Moringa oleifera has been used as an integral part of Ayurveda, Siddha and Unani systems of medicine, besides this miracle tree has a wide range of nutritional and bioactive compounds, including proteins, essential amino acids, carbohydrates, lipids, fiber, vitamins, minerals, phenolic compounds, phytosterols and others. The miracle tree is endowed with a wide range of pharmacological properties, including anti-diabetic, anti-inflammatory, anti-carcinogenic, antioxidant, cardioprotective, antimicrobial and hepatoprotective activities. However, deeper dimensions of authentic data on plant based natural products in relation to drug discovery, pharmacokinetics properties of biomolecules is far lacking. ADMET prospecting is eventually expected to contribute to success of MO based lead candidates in drug design, development program besides saving time and money. This study is the first of its kind reporting summative ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicology) properties of all bioactive compounds Moringa oleifera methanolic pod extract (MOMPE) as a potential source of natural drug lead using Swiss ADME. A total of 12 compounds namely - 7-Octadecyne, 2-methyl- (C19H36); 3,7,11,15-Tetramethyl-2-hexadecen-1-ol (C20H40O); 3,7,11,15-Tetramethyl-2-hexadecen-1-ol (C20H40O); 6,9,12,15-Docosatetraenoic acid, me (C23H38O2); Cyclohexanol, 5-methyl-2-(1-methylethyl)- (C10H20O); 3,7,11,15-Tetramethyl-2-hexadecen-1-ol (C20H40O); Palmitic acid vinyl ester (C18H34O2); .γ.-Tocopherol (C28H48O2); Vitamin E (C29H50O2); Cholesta-7,9(11)-dien-3-ol, 4,4-dim (C29H48O); γ.-Sitosterol (C29H50O); Stigmasta-5,24(28)-dien-3-ol, (3.β.,24Z)- (C29H48O). Most of the MOPBNPs are non-substrate for both P-gp (P-glycoprotein) and CYP (Cytochrome P-450 isoenzymes). All the compounds were evaluated for properties viz., GI absorption, BBB permeant, Pgp substrate, CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4 inhibitors, Lipinski, Ghose, Veber, Egan, Muegge, rule and Bioavailability Score to provide baseline information on PBNPs in MONRD pod.
 Keywords: PBNPs; NGDDT; ADMET; Moringa oleifera; Secondary Metabolites MONRD pod

Synthesis, Biocidal and Antibiofilm Activities of New Isatin-Quinoline Conjugates against Multidrug-Resistant Bacterial Pathogens along with Their In Silico Screening.

Isatin-quinoline conjugates 10a-f and 11a-f were assembled by the reaction of N-(bromobutyl) isatin derivatives 3a, b with aminoquinolines 6a-c and their corresponding hydrazinyl 9a-c in good yields. The structures of the resulting conjugates were established by spectroscopic tools and showed data consistent with the proposed structures. In vitro antibacterial activity against different bacterial strains was evaluated. All tested conjugates showed significant biocidal activity with lower MIC than the first line drugs chloramphenicol and ampicillin. Conjugates 10a, 10b and 10f displayed the most potent activity against all clinical isolates. The antibiofilm activity for all tested conjugates was screened against the reference drug vancomycin using the MRSA strain. The results revealed that all conjugates had an inhibitory activity against biofilm formation and conjugate. Conjugate 11a showed 83.60% inhibition at 10 mg/mL. In addition, TEM studies were used to prove the mechanism of antibacterial action of conjugates 10a and 11a against (MRSA). Modeling procedures were performed on 10a-f and 11a-f and interestingly the results were nearly consistent with the biological activities. In addition, in silico pharmacokinetic evaluation was performed and revealed that the synthesized compounds 10a-f and 11a-f were considered drug-like molecules with promising bioavailability and high GI absorption. The results confirmed that the title compounds caused the disruption of bacterial cell membranes and could be used as potential leads for the further development and optimization of antibacterial agents.

Cytotoxic Activity and Docking Studies of 2-arenoxybenzaldehyde N-acyl Hydrazone and 1,3,4-Oxadiazole Derivatives against Various Cancer Cell Lines.

To understand whether previously synthesized novel hydrazone and oxadiazole derivatives have promising anticancer effects, docking studies and in vitro toxicity assays were performed on A-549, MDA-MB-231, and PC-3 cell lines. The antiproliferative properties of the compounds were investigated using molecular docking experiments. Each compound's best-docked poses, binding affinity, and receptor-ligand interaction were evaluated. Compounds' molecular weights, logPs, TPSAs, abilities to pass the blood-brain barrier, GI absorption qualities, and CYPP450 inhibition have been given. When the activities of these molecules were examined in vitro, for the A-549 cell line, hydrazone 1e had the minimum IC50 value of 13.39 μM. For the MDA-MB-231 cell line, oxadiazole 2l demonstrated the lowest IC50 value, with 22.73 μM. For PC-3, hydrazone 1d showed the lowest C50 value of 9.38 μM. The three most promising compounds were determined as compounds 1e, 1d, and 2a based on their minimum IC50 values, and an additional scratch assay was performed for A-549 and MDA-MB-231 cells, which have high migration capacity, for the three most potent molecules; it was determined that these molecules did not show a significant antimetastatic effect.

Exploring Novel Pyridine Carboxamide Derivatives as Urease Inhibitors: Synthesis, Molecular Docking, Kinetic Studies and ADME Profile.

The rapid development of resistance by ureolytic bacteria which are involved in various life-threatening conditions such as gastric and duodenal cancer has induced the need to develop a new line of therapy which has anti-urease activity. A series of pyridine carboxamide and carbothioamide derivatives which also have some novel structures were synthesized via condensation reaction and investigated against urease for their inhibitory action. Among the series, 5-chloropyridine-2 yl-methylene hydrazine carbothioamide (Rx-6) and pyridine 2-yl-methylene hydrazine carboxamide (Rx-7) IC50 = 1.07 ± 0.043 µM, 2.18 ± 0.058 µM both possessed significant activity. Furthermore, molecular docking and kinetic studies were performed for the most potent inhibitors to demonstrate the binding mode of the active pyridine carbothioamide with the enzyme urease and its mode of interaction. The ADME profile also showed that all the synthesized molecules present oral bioavailability and high GI absorption.

Microwave assisted synthesis of 2-amino-4-chloro-pyrimidine derivatives: Anticancer and computational study on potential inhibitory action against COVID-19

We report microwave synthesis of seven unique pyrimidine anchored derivatives (1–7) incorporating multifunctional amino derivatives along with their in vitro anticancer activity and their activity against COVID-19 in silico. 1–7 were characterized by different analytical and spectroscopic techniques. Cytotoxic activity of 1–7 was tested against HCT116 and MCF7 cell lines, whereby 6 exhibited highest anticancer activity on HCT116 and MCF7 with EC50 values of 89.24 ± 1.36 µM and 89.37 ± 1.17 µM, respectively.Molecular docking was performed for derivatives (1–7) on main protease for SARS-CoV-2 (PDB ID: 6LU7). Results revealed that most of the derivatives had superior or equivalent affinity for the 3CLpro, as determined by docking and binding energy scores. 6 topped the rest with highest binding energy score of −8.12 kcal/mol with inhibition constant reported as 1.11 µM. ADME, drug-likeness, and pharmacokinetics properties of 1–7 were tested using Swiss ADME tool. Toxicity analysis was done with pkCSM online server.All derivatives showed high GI absorption. Except 1 and 3, all derivatives showed blood brain barrier permeability. Most derivatives showed negative logKp values suggesting derivatives are less skin permeable and bioavailability score of all derivatives was 0.55. The toxicity analysis demonstrated that all derivatives have no skin sensitization properties. 6 and 7 showed maximum tolerated dose (Human) values of −0.03 and −0.018, respectively and absence of AMES toxicity.

New Quinazolin-4(3H)-one Derivatives Incorporating Hydrazone and Pyrazole Scaffolds as Antimicrobial Agents Targeting DNA Gyraze Enzyme

The present work includes the synthesis of a new series of quinazolin-4(3H)-one compounds (4a–f, 5a–d) as antimicrobial agents. The starting compound, 2-hydrazinylquinazolin-4(3H)-one (2), was synthesized and treated with different carbonyl compounds to afford the hydrazone derivatives 4a–f. In addition, the hydrazone derivatives 4a–d were treated with a DMF/POCl3 mixture to give the formyl-pyrazole derivatives 5a–d. All the target compounds were evaluated as antimicrobial agents against four bacterial and four fungal strains. The majority of the tested compounds showed potent antimicrobial activity compared with the reference antibiotics. The most potent antimicrobial activity was shown by 5a with MIC values in the range (1–16) μg/mL. In addition, the most potent compounds against E. coli were evaluated for their inhibitory activity against E. coli DNA gyrase, whereas the target compounds 4a, 5a, 5c, and 5d showed the most potent inhibition to the target enzyme with IC50 values ranging from 3.19 to 4.17 µM. Furthermore, molecular docking studies were performed for the most active compounds against the target E. coli DNA gyrase to determine their binding affinity within the enzyme’s active site. Moreover, ADME evaluations of these compounds predicted their high oral bioavailability and good GI absorption.

Analisis Profil Fisika Kimia dan Farmakokinetik Senyawa Pentagamavunon-1 Secara Komputasi

Pentagamavunon-1 (PGV-1) is a curcumin analog which is known to inhibit the growth of cancer cells, bacteria and inhibit free radicals as an antioxidant agent. The purpose of this study was analyzed the pharmacokinetic profile and physicochemical properties of PGV-1 computationally. The predicted parameters were Lipinski rule of five, bioavailability, Blood Brain Barrier (BBB) ​​absorption, GI absorption, P-gp substrate, and prediction of metabolic enzymes involved in drug ADME processes. The results of this study indicate that the compound PGV-1 complies with the Lipinski rule of five with the characteristics of a molecular weight of 348.43 g/mol, hydrogen donor 2, hydrogen acceptor 3, Log P 4.71 and molar refractory 40-130. PGV-1 could absorb through the GI and can pass the blood brain barrier passively without P-gp protein. Several enzymes involved in the metabolism of PGV-1 are CYP2C19, CYP2C9, CYP 3A4. Thus, our finding suggest that PGV-1 can be developed as a drug target compound for active oral drugs.

IN SILICO ADME ANALYSIS AND MOLECULAR DOCKING APPLIED TO FLAVONOIDS TO FIND DRUG LEAD COMPOUNDS TARGETING DRD4

Objective: The aim of this present study is to find flavonoids that can be potential drug lead compounds targeting the human D(4) Dopamine receptor (DRD4). Thirty-nine flavonoids were collected from the literature survey, and 23 of them were predicted by SwissTargetPrediction to have bioactivity toward DRD4. Methods: ADME properties were evaluated, and molecular docking was executed. Among the flavonoids studied, Isovitexin, Glabridin, and Glabrone have shown better binding energy than the native ligand, Nemonapride. However, ADME analysis has demonstrated that Isovitexin has low GI absorption and is in the grey zone of the BOILED-egg. Glabridin is a BBB permeant but is a P-gp substrate. Glabrone has high GI absorption, and a P-gp non-substrate but not a BBB permeant. Results and Conclusion: The experimental investigations and clinical evaluations are recommended to examine the mechanisms of their actions and other pharmacological effects and to validate the results of this in silico study. The scaffolds of these compounds can also be optimized to improve the few lapses and have better attributes as CNS drug lead candidates.

Evaluation of the Cytotoxic Activity and Anti-Migratory Effect of Berberine-Phytantriol Liquid Crystalline Nanoparticle Formulation on Non-Small-Cell Lung Cancer In Vitro.

Non-small-cell lung cancer (NSCLC) is the most common form of lung cancer, which is a leading cause of cancer-related deaths worldwide. Berberine is an isoquinoline alkaloid that is commercially available for use as a supplement for the treatment of diabetes and cardiovascular diseases. However, the therapeutic benefits of berberine are limited by its extremely low bioavailability and toxicity at higher doses. Increasing evidence suggests that the incorporation of drug compounds in liquid crystal nanoparticles provides a new platform for the safe, effective, stable, and controlled delivery of the drug molecules. This study aimed to formulate an optimized formulation of berberine–phytantriol-loaded liquid crystalline nanoparticles (BP-LCNs) and to investigate the in vitro anti-cancer activity in a human lung adenocarcinoma A549 cell line. The BP-LCN formulation possessing optimal characteristics that was used in this study had a favorable particle size and entrapment efficiency rate (75.31%) and a superior drug release profile. The potential mechanism of action of the formulation was determined by measuring the mRNA levels of the tumor-associated genes PTEN, P53, and KRT18 and the protein expression levels with a human oncology protein array. BP-LCNs decreased the proliferation, migration, and colony-forming activity of A549 cells in a dose-dependent manner by upregulating the mRNA expression of PTEN and P53 and downregulating the mRNA expression of KRT18. Similarly, BP-LCNs also decreased the expression of proteins related to cancer cell proliferation and migration. This study highlights the utility of phytantriol-based LCNs in incorporating drug molecules with low GI absorption and bioavailability to increase their pharmacological effectiveness and potency in NSCLC.

Posaconazole oral suspension for secondary antifungal prophylaxis in allogeneic stem cell transplantation recipients: a retrospective study

BackgroundThere is no consensus on the optimal secondary antifungal prophylaxis (SAP) regimen in patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). The purpose of this study was to evaluate the efficacy and safety of posaconazole oral suspension as secondary prophylaxis of invasive fungal disease (IFD) for allo-HSCT patients.MethodsWe retrospectively reviewed clinical data from prior IFD patients who received posaconazole oral suspension as systemic antifungal prophylaxis between June 2016 and January 2021 and have a follow-up period of 1 year after HSCT. The clinical outcomes of patients with a prior history of IFD (n = 30) and those without (n = 93) were compared.ResultsThe 1-year cumulative incidence of prophylaxis failure was 58.3% in the group with prior history of IFD and 41.6% in the group without a prior history of IFD (p = 0.459). The cumulative incidence of proven, probable or possible IFD within 1 year after allo-HSCT was 23.1% in the group with prior history of IFD and 14.1% in the group without prior history of IFD (p = 0.230). There was no significant difference between the cumulative incidence of proven or probable IFD within 1-year after allo-HSCT in the group with a prior history of IFD and the group without (p = 0.807). Multivariate logistic regression revealed cytomegalovirus disease as risk factor for post-transplantation IFD occurrence in posaconazole oral suspension prophylaxis. There was not a significant difference in overall survival between the patients with IFD history and those without (P = 0.559).ConclusionsOur study support that allo-HSCT recipients with a prior history of IFD and normal GI absorption can choose posaconazole oral suspension as a safe and effective SAP option.

Synthesis, Biological Activity, and Molecular Modelling Studies of Naphthoquinone Derivatives as Promising Anticancer Candidates Targeting COX-2.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-associated mortalities worldwide. Therefore, it is crucial to develop a novel therapeutic option targeting localized and metastatic NSCLC. In this paper, we describe the synthesis and biological activity characterization of naphthoquinone derivatives bearing selective anticancer activity to NSCLC via a COX-2 mediated pathway. The biological evaluation of compounds 9–16 showed promising structure-dependent anticancer activity on A549 cells in 2D and 3D models. Compounds were able to significantly (p < 0.05) reduce the A549 viability after 24 h of treatment in comparison to treated control. Compounds 9 and 16 bearing phenylamino and 4-hydroxyphenylamino substituents demonstrated the most promising anticancer activity and were able to induce mitochondrial damage and ROS formation. Furthermore, most promising compounds showed significantly lower cytotoxicity to non-cancerous Vero cells. The in silico ADMET properties revealed promising drug-like properties of compounds 9 and 16. Both compounds demonstrated favorable predicted GI absorption values, while only 16 was predicted to be permeable through the blood–brain barrier. Molecular modeling studies identified that compound 16 is able to interact with COX-2 in arachidonic acid site. Further studies are needed to better understand the safety and in vivo efficacy of compounds 9 and 16.

Invasive Cytomegalovirus Disease in a Low Risk CMV Serostatus, D-/R- Lung Transplant Recipient

<h3>Introduction</h3> Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality among transplant patients. Here, we report a case of lung transplant patient with low risk CMV serostatus (D-/R-) who developed invasive CMV disease. <h3>Case Report</h3> A 64-year-old lady with COPD underwent bilateral lung transplant. CMV serostatus was donor IgG negative / recipient IgG negative. Basiliximab was used for induction and was maintained on tacrolimus, mycophenolate and prednisone. Intraoperatively, she received 2 leucoreduced PRBC's. 15 days post-transplant she developed CMV viremia and was started on treatment dose valganciclovir. No mutations noted on the resistance panel. 2 weeks on therapy, there was no reduction in the CMV PCR. Chest CT showed a right pleural effusion which was exudative in nature. Microbiology testing was negative. Fluid cytology showed CMV cytopathic changes. Valganciclovir was changed to iv ganciclovir because of her GI absorption concerns. With 6 weeks of iv ganciclovir and monthly CMV Immune globulin, CMV PCR log values steadily declined. <h3>Summary</h3> Lung transplant patients with low risk CMV serostatus can have a minor risk of transfusion acquired (TA) or community acquired (CA) CMV infection. A single center retrospective study of low-risk organ transplant patients did not identify any cases of TA CMV infection in patients receiving leucoreduced PRBC. Another study showed 2.4% risk of TA CMV infection in patients receiving non-leucoreduced PRBC. CA CMV risk is greater than TA CMV, with the incidence being higher in children (3/100 patient years) compared to adults (0.46/100 patient years). Currently no guidelines exist to recommend CMV prophylaxis in low risk CMV serostatus transplant patients. Hence measures need to be taken to monitor such patients who are at increased risk for TA or CA CMV. Recipients whose IgG was negative during transplant work up should be retested at the time of transplant. CMV PCR monitoring should be considered if the donor or recipient received extensive transfusions.

In Silico Evaluation of a Promising Key Intermediate Thieno [2,3-d] Pyrimidine Derivative with Expected JAK2 Kinase Inhibitory Activity

This work describes the synthesis and the cytotoxic evaluation of thiophene and thienopyrimidine derivatives. The investigated compound was subjected to target prediction that indicated its high affinity to kinases and to Janus kinase 2 (JAK2) specifically. Molecular docking screening was performed on three different JAK2 proteins downloaded from the Protein Data Bank (PDB: 5AEP, 4C62 and 3ZMM). In vitro kinase inhibitory activity was evaluated and then compound cytotoxicity was performed on three different cancerous cell lines (HT-29, HepG-2, and MCF-7). Marked cytotoxic activity of the thienopyrimidine derivative against the HepG-2 cell line was demonstrated, reflected by its IC50 value of 8.001 ± 0.0445 μM, which is better than that of the reference standard (IC50 13.91 ± 2.170 μM). Pharmacokinetic studies revealed good well permeability and GI absorption with no violations against Lipinski’s rule.

Natural Products as Novel Neuroprotective Agents; Computational Predictions of the Molecular Targets, ADME Properties, and Safety Profile.

Neurodegenerative diseases (NDs) are one of the most challenging public health issues. Despite tremendous advances in our understanding of NDs, little progress has been made in establishing effective treatments. Natural products may have enormous potential in preventing and treating NDs by targeting microglia; yet, there have been several clinical concerns about their usage, primarily due to a lack of scientific evidence for their efficacy, molecular targets, physicochemical properties, and safety. To solve this problem, the secondary bioactive metabolites derived from neuroprotective medicinal plants were identified and selected for computational predictions for anti-inflammatory activity, possible molecular targets, physicochemical properties, and safety evaluation using PASS online, Molinspiration, SwissADME, and ProTox-II, respectively. Most of the phytochemicals were active as anti-inflammatory agents as predicted using the PASS online webserver. Moreover, the molecular target predictions for some phytochemicals were similar to the reported experimental targets. Moreover, the phytochemicals that did not violate important physicochemical properties, including blood-brain barrier penetration, GI absorption, molecular weight, and lipophilicity, were selected for further safety evaluation. After screening 54 neuroprotective phytochemicals, our findings suggest that Aromatic-turmerone, Apocynin, and Matrine are the most promising compounds that could be considered when designing novel neuroprotective agents to treat neurodegenerative diseases via modulating microglial polarization.

In silico screening of chloroquine analogues for compounds with more affinity for the Plasmodium falciparum chloroquine transporter as potential antimalarial drugs

Background: Malaria is an acute febrile illness affecting over 229 million people worldwide. Children aged five years and below are affected the most, with the highest prevalence in Sub-Saharan Africa. Chloroquine was previously used as the first-line treatment for malaria due to its affordability and high efficacy, but resistance has developed. Resistance to chloroquine is due to a mutation in the protein Plasmodium falciparum Chloroquine Transporter (pfCRT) which effluxes the drug from the parasitic digestive vacuole, decreasing the drug concentration. Resistance has however been shown to be reversible by compounds that can bind to the protein. Methods: In silico screening for chloroquine analogues was done using SwissSimilarity, SWISSADME, SwissTargetPrediction, Pubchem sketcher, Chimera and Avogadro tools to predict pharmacodynamics and pharmacokinetic profiles of the selected analogues. Results: About 20 compounds with a similarity index of &gt; 95% were obtained from the ZINC database. In total, 12 of the 20 compounds showed a higher binding affinity to the mutant pfCRT protein. Overall, four of the 12 had a binding affinity less than -8.0 compared to -7.0 for chloroquine. Compound ZINC01596768 had the greatest binding strength at -8.3. The other analogues were ZINC38050614, ZINC38050617, and ZINC38050615 with binding interaction strengths of -8.0, -8.2 and -8.2 respectively. Pharmacokinetic profile prediction showed all 12 compounds inhibited the enzymes CYP1A2 and CYP2D6, followed the Lipinski rules, had a high GI absorption, were permeant to the blood brain barrier, had no alerts on the PAINS criteria and had violated the rule of XLOGP3 &gt; 3.5 in lead likeness. Compounds ZINC38050614, ZINC38050617, and ZINC38050615 were predicted to be substrates of P-glycoprotein. The synthetic accessibility score for the twelve compounds were below 3.07. Conclusions: Results demonstrated that the compounds ZINC01596768, ZINC38050614, ZINC38050617, and ZINC38050615 were potential candidates that could be tested and developed as co-formulations of chloroquine.