A series of 25 new chalcones were synthesized by Claisen-Schmidt condensation, well characterized by spectroscopic data, and evaluated for their antibacterial and antifungal activities by serial tube dilution method. Among the compounds tested, A3 and A6 containing 2,4-dichlorophenyl and 2,4-difluorophenyl moiety, respectively, were found to be the most potent in the series against both bacterial and fungal strains with a MIC value of 16&#x2009;&#xb5;g/mL in each case. Further computational evaluation for antimicrobial activity was performed by atom based 3D-QSAR using PHASE&#x2122; software in order to have a correlation between the observed activities and predicted activities. The computational studies were in agreement with the in vitro antimicrobial results and had identified the most promising chalcones as antimicrobial agents and the responsible structural features for the proposed activity.

Afzal Basha Shaik

Rajendra Prasad Yejella

Shahanaaz Shaik

Synthesis, Antimicrobial, and Computational Evaluation of Novel Isobutylchalcones as Antimicrobial Agents

Griseofulvin 1 is an important antifungal agent that has recently received attention due to its antiproliferative activity in mammalian cancer cells. Study of SAR of some griseofulvin analogues has led to the identification of 2&#x2032;-benzyloxy griseofulvin 3, a more potent analogue which retards tumor growth through inhibition of centrosomal clustering. However, similar to griseofulvin 1, compound 3 exhibited poor aqueous solubility. In order to improve the poor water solubility, six new griseofulvin analogues 5&#x2013;10 were synthesized and tested for their antiproliferative activity and water solubility. The semicarbazone 9 and aminoguanidine 10 analogues were the most potent against HCT116 and MCF-7 cell lines. In combination studies, compound 9 was found to exert synergistic effects with tamoxifen and 5-fluorouracil against MCF-7 and HCT116 cells proliferation, respectively. The flow cytometric analysis of effect of 9 on cell cycle progression revealed G2/M arrest in HCT116. In addition, compound 9 induced apoptosis in MCF-7 cells. Finally, all synthesized analogues revealed higher water solubility than griseofulvin 1 and benzyloxy analogue 3 in pH 1.2 and 6.8 buffer solutions.

Ahmed K. Hamdy

Mahmoud M. Sheha

Atef A. Abdel-Hafez

Samia A. Shouman

Design, Synthesis, and Cytotoxicity Evaluation of Novel Griseofulvin Analogues with Improved Water Solubility

The aim of this study was to evaluate complexes of L-ascorbyl palmitate (ASCP) and urea (UR). This evaluation involved differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), near-infrared spectroscopy (NIR), a solubility test, a 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging test, and a mushroom tyrosinase inhibition assay. Physicochemical evaluation revealed that ASCP/UR complexes form at a molar ratio of 1/12. The solubility test revealed that ASCP/UR complexes had increased solubility compared to ASCP. The DPPH radical scavenging test and mushroom tyrosinase inhibition assay revealed that the activity of ASCP/UR complexes was not impaired by complex formation. These results are probably due to the tetragonal crystal system of UR changing to a hexagonal crystal system and interaction with the alkyl group of ASCP.

Yutaka Inoue

Daichi Niiyama

Isamu Murata

Ikuo Kanamoto

Usefulness of Urea as a Means of Improving the Solubility of Poorly Water-Soluble Ascorbyl Palmitate

Antagonism of the adenosine <svg xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg" style="vertical-align:-3.181499pt" id="M1" height="11.9479pt" version="1.1" viewBox="-0.0498162 -8.7664 20.484 11.9479" width="20.484pt"><g transform="matrix(.013,0,0,-0.013,0,0)"><path id="g121-63" d="M673 0V28C608 34 594 43 563 129C499 303 432 494 370 665L339 656L132 132C98 43 84 37 20 28V0H238V28C162 35 154 45 175 108C188 150 203 192 219 237H432C454 176 474 122 487 83S491 36 428 28V0H673ZM418 280H234C265 362 296 450 328 535H330L418 280Z"/></g><g transform="matrix(.0091,0,0,-0.0091,8.983,3.132)"><path id="g50-51" d="M414 144C384 79 371 75 317 75H135L276 221C367 316 408 376 408 465C408 570 327 635 237 635C179 635 131 609 100 575L42 494L67 471C94 510 138 565 205 565C277 565 321 517 321 435C321 348 258 270 195 195C146 137 88 81 33 26V0H411C423 44 433 88 446 135L414 144Z"/></g><g transform="matrix(.0091,0,0,-0.0091,13.415,3.132)"><path id="g58-63" d="M682 0V33C615 38 603 49 571 134C507 305 441 494 378 665L343 655L136 136C101 48 86 41 22 33V0H246V33C170 41 161 50 183 112C196 152 209 192 224 232H441C461 176 478 126 493 87C504 49 499 41 433 33V0H682ZM425 279H242C273 363 303 448 335 533H337L425 279Z"/></g></svg> receptor on T cells blocks the hypoxia-adenosinergic pathway to promote tumor rejection. Using an in vivo immunoassay based on the Concanavalin A mouse model, a series of <svg xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg" style="vertical-align:-3.181499pt" id="M2" height="11.9479pt" version="1.1" viewBox="-0.0498162 -8.7664 20.484 11.9479" width="20.484pt"><g transform="matrix(.013,0,0,-0.013,0,0)"><use xlink:href="#g121-63"/></g><g transform="matrix(.0091,0,0,-0.0091,8.983,3.132)"><use xlink:href="#g50-51"/></g><g transform="matrix(.0091,0,0,-0.0091,13.415,3.132)"><use xlink:href="#g58-63"/></g></svg> antagonists were studied and identified preladenant as a potent lead compound for development. Molecular modeling was employed to assist drug design and subsequent synthesis of analogs and those of tozadenant, including fluorinated polyethylene glycol PEGylated derivatives. The efficacy of the analogs was evaluated using two in vitro functional bioassays, and compound 29, a fluorinated triethylene glycol derivative of preladenant, was confirmed as a potential immunotherapeutic agent.

Gengyang Yuan

Tanner C. Jankins

Christopher G. Patrick

Phaethon Philbrook

Olivia Sears

Stephen Hatfield

Michail Sitkovsky

Neil Vasdev

Steven H. Liang

Mary Jo Ondrechen

Michael P. Pollastri

Graham B. Jones

Fluorinated Adenosine A2A Receptor Antagonists Inspired by Preladenant as Potential Cancer Immunotherapeutics

Thiazolidinediones are a class of well-established antidiabetic drugs, also named as glitazones. Thiazolidinedione structure has been an important structural domain of research, involving design and development of new drugs for the treatment of type 2 diabetes. Extensive research on the mechanism of action and the structural requirements has revealed that the intended antidiabetic activity in type 2 diabetes is due to their agonistic effect on peroxisome proliferator-activated receptor (PPAR) belonging to the nuclear receptor super family. Glitazones have specific affinity to PPAR&#x3b3;, one of the subtypes of PPARs. Certain compounds under development have dual PPAR&#x3b1;/&#x3b3; agonistic activity which might be beneficial in obesity and diabetic cardiomyopathy. Interesting array of hybrid compounds of thiazolidinedione PPAR&#x3b3; agonists exhibited therapeutic potential beyond antidiabetic activity. Pharmacology and chemistry of thiazolidinediones as PPAR&#x3b3; agonists and the potential of newer analogues as dual agonists of PPARs and other emerging targets for the therapy of type 2 diabetes are presented. This review highlights the possible modifications of the structural components in the general frame work of thiazolidinediones with respect to their binding efficacy, potency, and selectivity which would guide the future research in design of novel thiazolidinedione derivatives for the management of type 2 diabetes.

Neelaveni Thangavel

Mohammed Al Bratty

Sadique Akhtar Javed

Waquar Ahsan

Hassan A. Alhazmi

Targeting Peroxisome Proliferator-Activated Receptors Using Thiazolidinediones: Strategy for Design of Novel Antidiabetic Drugs

Although membrane proteins represent most therapeutically relevant drug targets, the availability of atomic resolution structures for this class of proteins has been limited. Structural characterization has been hampered by the biophysical nature of these polytopic transporters, receptors, and channels, and recent innovations to in vitro techniques aim to mitigate these challenges. One such class of membrane proteins, the ATP-binding cassette (ABC) superfamily, are broadly expressed throughout the human body, required for normal physiology and disease-causing when mutated, yet lacks sufficient structural representation in the Protein Data Bank. However, recent improvements to biophysical techniques (e.g., cryo-electron microscopy) have allowed for previously &#x201c;hard-to-study&#x201d; ABC proteins to be characterized at high resolution, providing insight into molecular mechanisms-of-action as well as revealing novel druggable sites for therapy design. These new advances provide ample opportunity for computational methods (e.g., virtual screening, molecular dynamics simulations, and structure-based drug design) to catalyze the discovery of novel small molecule therapeutics that can be easily translated from computer to bench and subsequently to the patient&#x2019;s bedside. In this review, we explore the utility of recent advances in biophysical methods coupled with well-established in silico techniques towards drug development for diseases caused by dysfunctional ABC proteins.

Steven V. Molinski

Zolt&#xe1;n Boz&#xf3;ky

Surtaj H. Iram

Saumel Ahmadi

Biophysical Approaches Facilitate Computational Drug Discovery for ATP-Binding Cassette Proteins

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International Journal of Medicinal Chemistry publishes original research articles as well as review articles in all areas of chemistry associated with drug discovery, design, and synthesis.

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International Journal of Medicinal Chemistry ceased publication in 2020 and is no longer accepting submissions.

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International Journal of Medicinal Chemistry

International Journal of Medicinal Chemistry publishes original research articles as well as review articles in all areas of chemistry associated with drug discovery, design, and synthesis.

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International Journal of Medicinal Chemistry