Medicinal and Pharmaceutical Chemistry Commons^™

Potent And Selective Small Molecule Mcl-1 Inhibitor Demonstrates Anti-Myeloma Activity And Overcomes Chemotherapy Resistance, Omar Sami Faleh Al-Odat

Theses and Dissertations

Despite a record number of clinical studies investigating various anti-myeloma treatments, the 5-year survival rate for multiple myeloma (MM) patients in the US is only 55%, and nearly all patients relapse. Poor patient outcomes demonstrate that myeloma cells are "born to survive” which means they can adapt and evolve following treatment. Thus, new therapeutic approaches to combat survival mechanisms and target treatment resistance are required. Importantly, Mcl-1, anti-apoptotic protein, is required for the development of MM and treatment resistance. This study looks at the possibility of KS18, a selective Mcl-1 inhibitor, to treat MM and overcome resistance. Our investigation demonstrates …

Mechanistic Study Of Antimicrobial Effectiveness Of Cyclic Amphipathic Peptide [R4W4] Against Methicillin-Resistant Staphylococcus Aureus Clinical Isolates, Ajayi David Akinwale, Keykavous Parang, Rakesh Kumar Tiwari, Jason Yamaki

Pharmacy Faculty Articles and Research

Antimicrobial peptides (AMPs) are being explored as a potential strategy to combat antibiotic resistance due to their ability to reduce susceptibility to antibiotics. This study explored whether the [R₄W₄] peptide mode of action is bacteriostatic or bactericidal using modified two-fold serial dilution and evaluating the synergism between gentamicin and [R₄W₄] against Escherichia coli (E. coli) and methicillin-resistant Staphylococcus aureus (MRSA) by a checkered board assay. [R₄W₄] exhibited bactericidal activity against bacterial isolates (MBC/MIC ≤ 4), with a synergistic effect with gentamicin against E. coli (FICI = 0.3) but …

Mechanistic Insight Into The Mode Of Inhibition Of Dietary Flavonoids; Targeting Macrophage Migration Inhibitory Factor, Ali Raza Siddiqui, Mamona Mushtaq, Madiha Sardar, Lubna Atta, Mohammad Nur-E-Alam, Aftab Ahmad, Zaheer Ul-Haq

Pharmacy Faculty Articles and Research

Introduction: The Macrophage Migration Inhibitory Factor (MIF), a key pro-inflammatory mediator, is responsible for modulating immune responses. An array of inflammatory and autoimmune diseases has been linked to the dysregulated activity of MIF. The significance in physiological as well as pathophysiological phenomena underscores the potential of MIF as an attractive target with pharmacological relevance. Extensive research in past has uncovered a number of inhibitors, while the ISO-1, or (S, R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester being recognized as a benchmark standard so far. Recent work by Yang and coworkers identified five promising dietary flavonoids, with superior activity compared to the standard …

Design, Synthesis, And Biological Evaluation Of Novel Heterocyclic Compounds For The Treatment Of Cancer And Neurodegenerative Disorders, Saloni Patel

Electronic Theses and Dissertations

Alzheimer's disease (AD) is a progressive neurodegenerative disease that impairs memory and cognitive judgment, mostly in older people. It is the leading cause of dementia in late adult life. The hallmarks of AD include neuronal loss, neuroinflammation, a build-up of extracellular amyloid beta (Aβ) plaques, intracellular neurofibrillary tangles, and extracellular neuritic plaques. Current treatment, although useful, is not adequate. Identification of therapeutic agents with the potential to alter the progress of AD is a high priority. Recent studies suggest that the Sigma-2 receptor is an attractive target for the development of disease-modifying AD drugs. Preventing the binding of Sigma-2 receptors …

Basic Structure Of The Pharmacophore Virtual Screening Protein 7kg7 For Candidate Therapeutic Options Covid-19, Ahmad Ridha Al Fiqri

Indonesian Journal of Medical Chemistry and Bioinformatics

Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome, namely coronaviruses (SARS-CoV-2) has been a pandemic to date and is contagious with relatively high mortality rates. Various efforts have been made to control the pandemic to finding the best solution to reduce the spread such as rapid detection based on molecular and serological, as well as efforts to find the best medicine for COVID-19 patients continue to be carried out. We analyzed and concluded that the presatovir compound is capable of being a substitute for the native protein ligand 7KG7, this is proved with a ΔG value of -13.22 kcal/mol …

Targeting Cancer- One Carbon At A Time: Design And Synthesis Of Pyrimidine Based Heterocycles As Potential Cancer Chemotherapeutics, Md Junayed Nayeen

Electronic Theses and Dissertations

With over 6 million death counts, cancer is the second leading cause of death in the United States. Lung cancer was the leading cause of cancer death, accounting for 23% (136,084 death count) of all cancer deaths. Other than that, colon and rectal (9%, 51,869 death count), pancreas (8%, 46,774 death count), female breast (7%, 42,275 death count), prostate (5%, 32,707 death count), and liver and intrahepatic bile duct (5%, 28,227 death count). Other cancers individually accounted for less than 5% of cancer deaths. Although cancer death rates decreased about 27% from 2001 to 2020, the therapeutic options are limited …

An Integrative Review Of The Absorption Of Fda-Approved Chemical Sunscreen Filters Into The Blood, Srinidhi Banala, Samrat Gollapudi, Abhiram Gollapudi, Bhaumik Patel

Rowan-Virtua Research Day

Introduction: This integrative review examines the absorption of FDA-approved chemical sunscreen filters, specifically avobenzone and oxybenzone, into the bloodstream. The study aims to compare the levels of absorption and potential health effects of systemic exposure to these sunscreen ingredients in the United States.

Methods: The researchers conducted a literature search of 57 articles, of which 15 were used for the review. Inclusion criteria focused on studies discussing absorption levels of avobenzone and oxybenzone, as well as methods of absorption into the bloodstream. Exclusion criteria included sunscreen ingredients not approved in the United States, non-English studies, and studies on methods to …

Investigating Effects Of Co-Culturing With Vibrio Fischeri On Secondary Metabolite Production Of Hawaiian Bobtail Squid Symbionts, Mariam A. Zedan

Honors Scholar Theses

Microbes are a fruitful source of natural product drug discovery since many of their secondary metabolites show defensive activity and have unique structures. However, extracting and elucidating the structure of those compounds can be challenging in vitro due to particular environmental and nutritional requirements of some bacteria. Those requirements may include proximity to other organisms that the microbes have symbiotic relationships with. Under those conditions, the organism may activate silent biosynthetic gene clusters (BGCs) responsible for production of certain secondary metabolites not typically expressed otherwise. One method of BGC induction is co-culturing with other microbes since this mimics the natural …

Amphipathic Hybrid Cyclic-Linear Peptides As A Drug Delivery System, Jonathan Moreno

Pharmaceutical Sciences (PhD) Dissertations

Amphipathic Hybrid Cyclic-Linear Peptides as a Drug Delivery System by Jonathan A. Moreno Peptides

[RW]₄ and [R₅W₄] have been previously identified as molecular transporter Cell Penetrating Peptide (CPP) and antimicrobial agents, respectively. These peptides consisted of alternating and non-alternating arginine (R) as positively charged residues and tryptophan (W) as hydrophobic residues. Herein we report the synthesis of two hybrid amphipathic cyclic-linear cell-penetrating peptides [RW]₄K-AH135 (1) and [R₅W₄]K-AH135 (2) composed of [RW]₄ and [R₅W₄] and a linear peptide AH-135 (Ac)NH-RWLRRWLRWWRR-COOH. The …

Synthesis Of Thermoresponsive Poly(N-Isopropyl Acrylamide) Based Core-Shell And Hollow Shell Nanogel With Tunable Core And Shell Thickness, Mohamad Hijazi, Molla R. Islam

Student Scholar Symposium Abstracts and Posters

Nanogels have emerged as a notably safer and more effective means for drug delivery, primarily due to their adjustable drug-loading capabilities. Hollow-core nanoparticles offer some unique properties that are desirable for drug delivery applications. Initially, silica core nanoparticles were synthesized using the Stöber process at different temperatures where Tetraethoxysilane (TEOS) undergoes hydrolysis in the presence of ethanol and then a condensation reaction to form silica nanoparticles. Scanning Electron Microscopy (SEM) and Optical Microscopy (OM) analysis revealed that the size of silica core particles varied with the synthesis temperature (300 nm at 30°C to 150 at 60°C). The core silica particles …

Predicting Ffar4 Agonists Using Structure-Based Machine Learning Approach Based On Molecular Fingerprints, Zaid Anis Sherwani, Syeda Sumayya Tariq, Mamona Mushtaq, Ali Raza Siddiqui, Mohammad Nur-E-Alam, Aftab Ahmed, Zaheer Ul-Haq

Pharmacy Faculty Articles and Research

Free Fatty Acid Receptor 4 (FFAR4), a G-protein-coupled receptor, is responsible for triggering intracellular signaling pathways that regulate various physiological processes. FFAR4 agonists are associated with enhancing insulin release and mitigating the atherogenic, obesogenic, pro-carcinogenic, and pro-diabetogenic effects, normally associated with the free fatty acids bound to FFAR4. In this research, molecular structure-based machine-learning techniques were employed to evaluate compounds as potential agonists for FFAR4. Molecular structures were encoded into bit arrays, serving as molecular fingerprints, which were subsequently analyzed using the Bayesian network algorithm to identify patterns for screening the data. The shortlisted hits obtained via machine learning protocols …

Broad-Spectrum Activity Of Membranolytic Cationic Macrocyclic Peptides Against Multi-Drug Resistant Bacteria And Fungi, Sandeep Lohan, Anastasia G. Konshina, Rakesh K. Tiwari, Roman G. Efremov, Innokentiy Maslennikov, Keykavous Parang

Pharmacy Faculty Articles and Research

The emergence of multidrug-resistant (MDR) strains causes severe problems in the treatment of microbial infections owing to limited treatment options. Antimicrobial peptides (AMPs) are drawing considerable attention as promising antibiotic alternative candidates to combat MDR bacterial and fungal infections. Herein, we present a series of small amphiphilic membrane-active cyclic peptides composed, in part, of various nongenetically encoded hydrophilic and hydrophobic amino acids. Notably, lead cyclic peptides 3b and 4b showed broad-spectrum activity against drug-resistant Gram-positive (MIC = 1.5–6.2 µg/mL) and Gram-negative (MIC = 12.5–25 µg/mL) bacteria, and fungi (MIC = 3.1–12.5 µg/mL). Furthermore, lead peptides displayed substantial antibiofilm action comparable …

Beyond Mitragynine: Composition Survey And Stability Assessment Of Kratom Tea Ordered Via Food Delivery Platforms In Bangkok, Thailand, Yuta Tokuda, Apinya Tubtimrattana, Nat Tansrisawad, Kornvalee Meesilpavikkai, Parath Thirati

Chulalongkorn Medical Journal

Background: Kratom is a native tree to Southeast Asia. Kratom leaves have long been used medicinally and recreationally due to their stimulative and opioid-like effects attributed to high endogenous levels of mitragynine and related alkaloids. Kratom is widely consumed as tea and is now publicly sold, including on food delivery platforms, after recent decriminalization despite selling of kratom products being still considered illegal by other acts.

Objectives: To assess the formulas of kratom teas sold on Thai food delivery platform together with their consistency and the stability of refrigerated teas.

Methods: Kratom alkaloids, mitragynine and 7-hydroxymitragynine, and additive contents of …

Identification And Characterization Of Novel, Small Molecule Inhibitors Of Spermine Oxidase, Amelia Bryn Furbish

MUSC Theses and Dissertations

The major intracellular polyamines spermine and spermidine are abundant endogenous compounds that are essential for cellular growth and development. Dysregulation of polyamine metabolism has been implicated as a key mechanism of injury across multiple forms of clinically challenging pathologies. Of the enzymes within the polyamine pathway, the catabolic enzyme spermine oxidase (SMOX) is of particular interest as it is subject to induction in response to infection, neuronal excitotoxicity, ischemia, and oxidative stress. In addition to the loss of radical scavenging capabilities associated with spermine depletion, catabolism of spermine by SMOX results in the production of toxic byproducts, including H_{2 …}

Impact Of Blender Type On Tribocharging In Pharmaceutical Powders Using Surface Modified V-Blender, Ami Shah

Honors Scholar Theses

Powders are a vital component of the pharmaceutical industry as they provide the basis for many solid dosage forms like tablets and capsules. Although, when using powders a common challenge is electrostatic charge accumulation due to numerous particle-particle and particle-wall collisions. This accumulated charge can lead then to poor powder homogeneity and compromised powder flow properties. In this study, tribocharging of pharmaceutical powders was analyzed using various V-blenders and mixing times . The evaluated blenders include: Aluminum, Polyvinyl Chloride (PVC), and surface modified Aluminum-PVC. Using the blenders, the model drug, Ibuprofen, was processed for different time intervals such as 5, …

An Injectable In Situ Forming Collagen/Alginate/Caso4 Composite Hydrogel For Tissue Engineering Applications: Optimization, Characterization And In Vitro Assessments, Samar A. Salim, Samar A. Salim

Nanotechnology Research Centre

In situ injectable hydrogels are effectively employed to fill irregular cavitary bone defects with initiating bone growth in targeted areas. Herein, an injectable composited hydrogel composed of collagen and alginate cross-linked in situ using different concentrations of calcium sulfate (0.15, 0.3 and 0.6%, wt./v) was synthesized. Recently, CaSO4 is frequently supported as a bone graft material for bone regeneration, owing to its biocompatibility and osteoconductive properties. Moreover, hydroxyapatite (Hap) after salinization-step by (3-Aminopropyl) triethoxysilane (APTES) was incorporated for further enhancing the osteoconductive property of injected hydrogels. All fabricated hydrogels were characterized by SEM, FTIR and XRD analyses. While physiochemical characteristics …

Smart Spectrophotometric Approaches For Estimation Of Difluprednate In Existence Of Its Synthetic Precursor And Alkaline Degradation Product; Comparative Statistical Studies And Analytical Ecological Appraisal, Heidi R. Abd El-Hadi, Basma M. Eltanany, Hala E. Zaazaa, Maya S. Eissa

Bulletin of Faculty of Pharmacy Cairo University

Scientists are currently attempting to lessen the harmful effects that chemicals and solvents have on the environment. The current work suggests four sensitive and sustainable spectrophotometric techniques for quantifying difluprednate (DIF) in presence of hydrocortisone acetate, which is a synthetic precursor of DIF, and in the presence of DIF alkaline degradation product. These methods are dual wavelength, fourier self-deconvolution, first derivative, and double divisor derivative ratio. The linearity range for all methods was 15.00-40.00 µg/mL. There is no statistically significant difference between established and reported methods, and the suggested strategies are more environmentally friendly than the reported one.

Mechanistic Investigation Of C—C Bond Activation Of Phosphaalkynes With Pt(0) Complexes, Roberto M. Escobar, Abdurrahman C. Ateşin, Christian Müller, William D. Jones, Tülay Ateşin

Research Symposium

Carbon–carbon (C–C) bond activation has gained increased attention as a direct method for the synthesis of pharmaceuticals. Due to the thermodynamic stability and kinetic inaccessibility of the C–C bonds, however, activation of C–C bonds by homogeneous transition-metal catalysts under mild homogeneous conditions is still a challenge. Most of the systems in which the activation occurs either have aromatization or relief of ring strain as the primary driving force. The activation of unstrained C–C bonds of phosphaalkynes does not have this advantage. This study employs Density Functional Theory (DFT) calculations to elucidate Pt(0)-mediated C–CP bond activation mechanisms in phosphaalkynes. Investigating the …

Modulation Of Hippocampal Protein Expression By A Brain Penetrant Biologic Tnf-Α Inhibitor In The 3xtg Alzheimer’S Disease Mice, Nataraj Jagadeesan, G. Chuli Roules, Devaraj V. Chandrashekar, Joshua Yang, Sanjana Kolluru, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Background

Biologic TNF-α inhibitors (bTNFIs) can block cerebral TNF-α in Alzheimer’s disease (AD) if these macromolecules can cross the blood–brain barrier (BBB). Thus, a model bTNFI, the extracellular domain of type II TNF-α receptor (TNFR), which can bind to and sequester TNF-α, was fused with a mouse transferrin receptor antibody (TfRMAb) to enable brain delivery via BBB TfR-mediated transcytosis. Previously, we found TfRMAb-TNFR to be protective in a mouse model of amyloidosis (APP/PS1) and tauopathy (PS19), and herein we investigated its effects in mice that combine both amyloidosis and tauopathy (3xTg-AD).

Methods

Eight-month-old female 3xTg-AD mice were injected intraperitoneally with …

A Novel Micropeptide, Slitharin, Exerts Cardioprotective Effects In Myocardial Infarction, Ahmed G. E. Ibrahim, Alessandra Ciullo, Shukuro Yamaguchi, Chang Li, Travis Antes, Xaviar Jones, Liang Li, Ramachandran Murali, Innokentiy Maslennikov, Niveda Sundararaman, Daniel Soetkamp, Eugenio Cingolani, Jennifer Van Eyk, Eduardo Marbán

Pharmacy Faculty Articles and Research

Purpose: Micropeptides are an emerging class of proteins that play critical roles in cell signaling. Here, we describe the discovery of a novel micropeptide, dubbed slitharin (Slt), in conditioned media from Cardiosphere-derived cells (CDCs), a therapeutic cardiac stromal cell type.

Experimental design: We performed mass spectrometry of peptide-enriched fractions from the conditioned media of CDCs and a therapeutically inert cell type (human dermal fibrobasts). We then evaluated the therapeutic capacity of the candidate peptide using an in vitro model of cardiomyocyte injury and a rat model of myocardial infarction.

Results: We identified a novel 24-amino acid micropeptide …