Mai E. Shoman

A new group of thiazolidine-2,4-dione derivatives of ciprofloxacin having butyryl linker 3a-l was synthesized via an alkylation of thiazolidine-2,4-diones with butyryl ciprofloxacin with yield range 48–77% andfully characterized by various spectroscopic and analytical tools. Anti-cancer screening outcomes indicated that 3a and 3i possess antiproliferative activities against human melanoma LOX IMVI cancer cell line with IC₅₀ values of 26.7 ± 1.50 and 25.4 ± 1.43 µM, respectively, using doxorubicin and cisplatin as positive controls with an IC₅₀ of 7.03 ± 0.40 and 5.07 ± 0.29 µM, respectively. Additionally, compound 3j showed promising anticancer activity against human renal cancer A498 cell line with IC₅₀ value of 33.9 ± 1.91 µM while doxorubicin and cisplatin showed IC₅₀ values of 3.59 ± 0.20 and 7.92 ± 0.45, respectively. On the other hand, compound 3i did not show considerable anti-bacterial activity against S. aureus, E. coli and P. aeruginosa, and only moderate activity against K. pneumoniae with only a tenth of the activity of ciprofloxacin, confirming the cytotoxicity observed. Mechanistically, compound 3i inhibited both topoisomerase I and II with IC₅₀ of 4.77 ± 0.26 and 15 ± 0.81 µM. Furthermore, it induced cell cycle arrest at S phase in melanoma LOX IMVI cells. Moreover, 3i provoked substantial levels of early, late apoptosis and necrosis in melanoma LOX IMVI cell line comparable to that induced by doxorubicin. Furthermore, compound 3i increased the expression level of active caspase-3 by 49 folds higher in LOX IMVI cell, increased protein expression level of Bax more than the control by 3 folds and inhibited PARP-1by 33% in LOX IMVI. All results were supported by theoretical docking studies on both tested enzymes confirming potential cytotoxicity for the synthesized hybrids.

With increasing longevity globally, the search for effective and patient-friendly anti-aging solutions has been growing. Retinoic acid (Ret) is an FDA-approved anti-aging and anti-wrinkling formula, however, its poor solubility and poor tolerability hamper its use in cosmetically accepted formulations. In this study, cyclodextrins and arginine were investigated for improving the solubility and tolerability of retinoic acid through the formation of inclusion complexes and salt formation, respectively. Two different methods were employed: physical mixing and kneading. The prepared dispersions were investigated for molecular docking (MD), solubility, thermal and spectral analyses, cytotoxicity, and scratch assays. The optimized disperse systems were formulated in a gel formulation and characterized for rheological, in vitro release, and kinetics. The MD, DSC, and FTIR results indicated that both β- and hydroxy propyl (HP) β-cyclodextrins could host RA in their cavities and form inclusion complexes. Ret can form a salt with the basic amino acid arginine. Solubility studies of RA significantly (p < 0.01) enhanced by 14- to 81-fold increases with the investigated cyclodextrins and arginine. The cell viability recorded for Ret:HP β-CD K and Ret:arginine K was significantly increased compared to that for Ret alone. The IC50% recorded for azelaic acid (mild to non-irritant control), Ret, Ret:HP β-CD K, and Ret:arginine K were 1000, 485, 1100, and 895 µg/mL, respectively. The two carriers (HP β-CD and the amino acid arginine) were able to significantly (p < 0.05) reduce the irritation potential of Ret. Furthermore, comparable gap closure rates were recorded for Ret alone, Ret:HP β-CD K, and Ret:arginine K, indicating that inclusion complexation and ion pair formation reduced the irritation potentials without undermining the efficacy.

Sixteen chemically varied metabolites were isolated from the bulbs of Hippeastrum vittatum (L'Her.) Herb., including eight flavonoids [3'-methyl isoliquiritigenin (2), 7-hydroxyflavan (8), 7-hydroxyflavanone (9), 7-hydroxyflavan-3-ol (10), 7-methoxy-3',4'-methylenedioxyflavan-3-ol (11), 7-hydroxy-3',4'-methylenedioxy flavan (12), 2',4'-dihydroxy-3'-methyl-3,4-methylenedioxychalcone (13), and isoliquiritigenin (14)], four acetophenones [2,6-dimethoxy-4-hydroxyacetophenone (3), 2,4-dihydroxyacetophenone (4), 2,4-dihydroxy-6-methoxy-3-methylacetophenone (6), and 2,4,6-trimethoxyacetophenone (7)], two alkaloids [lycorine (1) and narciprimine (15)], one phenol derivative [p-nitrophenol (5)], and one steroid [β-sitosterol 3-O-β-glucopyranoside (16)]. Their structures were elucidated by combining one- and two-dimensional NMR and ESI-MS techniques and by comparison with the reported literature data and some authentic samples. Except for lycorine (1), the isolated metabolites were obtained herein for the first time from Hippeastrum plants, among which compound 13 was identified as a new chalcone derivative. Additionally, the total phenolic and flavonoid contents of the total ethanol extract and different fractions of the bulbs were determined by the Folin-Ciocalteu and aluminum chloride colorimetric methods, respectively, whereas their antioxidant potential was compared using the phosphomolybdenum and 2,2'-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assays. Finally, the binding affinities of compounds 1-16 to some key target proteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), namely, main protease (M^pro), papain-like protease (PLpro), and RNA-dependent RNA polymerase (RdRp), were screened and compared using molecular docking analysis. The possible chemotaxonomic significance of the identified metabolites was also discussed.

Thiazolidinedione (TZD) is one of the privileged heterocyclic rings and has shown many biological applications in medicinal chemistry and drug discovery. This review covers the synthetic approaches of TZD and its derivatives, different synthetic techniques for affording the desired regioselectivity and stereoselectivity, and the techniques that would enhance reaction conditions such as microwave, one‐pot, or ultrasound synthesis. It focuses on synthetic challenges of glitazones and the transformation of other heterocycles to TZD. Moreover, the chemical and biological behavior of TZD through the substitution in the N3 position, modification of the C5 position, annealing in complex heterocyclic systems, and hybridization with other pharmacologically attractive moieties are discussed. All reactions mentioned are provided as possible with different reaction conditions, mechanisms, derivatives scope, yield and clarified by applications of such reactions in the construction of potential medicinal agents. The review also answers questions about rapid racemization of glitazones, their toxicity, considering TZD as pan‐assay interference compounds (PAINS) or not, and the influence of saturation of 5‐position of TZD in their biological activities. This review is a comprehensive guide to make informed decisions for construction of TZD derivatives with biological potentials.

Since its introduction to the market in the 1970s, ketoprofen has been widely used due to its high efficacy in moderate pain management. However, its poor solubility and ulcer side effects have diminished its popularity. This study prepared forms of ketoprofen modified with three basic excipients: tris, L-lysine, and L-arginine, and investigated their ability to improve water solubility and reduce ulcerogenic potential. The complexation/salt formation of ketoprofen and the basic excipients was prepared using physical mixing and coprecipitation methods. The prepared mixtures were studied for solubility, docking, dissolution, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), in vivo evaluation for efficacy (the writhing test), and safety (ulcerogenic liability). Phase solubility diagrams were constructed, and a linear solubility (AL type) curve was obtained with tris. Docking studies suggested a possible salt formation with L-arginine using Hirshfeld surface analysis. The order of enhancement of solubility and dissolution rates was as follows: L-arginine > L-lysine > tris. In vivo analgesic evaluation indicated a significant enhancement of the onset of action of analgesic activities for the three basic excipients. However, safety and gastric protection indicated that both ketoprofen arginine and ketoprofen lysine salts were more favorable than ketoprofen tris.

Curcumin is a natural polyphenolic compound with well-known anticancer properties. Poor solubility and permeability hamper its use as an anticancer pharmaceutical product. In this study, L-arginine, a basic amino acid and a small hydrophilic molecule, was utilized to form a salt with the weak acid curcumin to enhance its solubility and potentiate the anticancer activities of curcumin. Two methods were adopted for the preparation of curcumin: L-arginine salt, namely, physical mixing and coprecipitation. The ion pair or salt was characterized for docking, solubility, DSC, FTIR, XRD, in vitro dissolution, and anticancer activities using MCF7 cell lines. The molecular docking suggested a salt/ion-pair complex between curcumin and L-arginine. Curcumin solubility was increased 335- and 440-fold by curcumin in L-arginine, physical, and co-precipitated mixtures, respectively. Thermal and spectral analyses supported the molecular docking and formation of a salt/ion pair between curcumin and L-arginine. The cytotoxicity of curcumin L-arginine salt significantly improved (p < 0.05) by 1.4-fold, as evidenced by the calculated IC_50%, which was comparable to Taxol (the standard anticancer drug but with common side effects).

FMS‐like tyrosine kinase 3 (FLT3) mutations occur in approximately 30% of acute myeloid leukemia (AML) patients. In the current study, the oxindole chemotype is employed as a structural motif for the design of new FLT3 inhibitors as potential hits for AML irradiation. Cell‐based screening was performed with 18 oxindole derivatives and 5a–c inhibited 68%–73% and 83%–91% of internal tandem duplication (ITD)‐mutated MV4‐11 cell growth for 48‐ and 72‐h treatments while only 0%–2% and 27%–39% in wild‐type THP‐1 cells. The most potent compound 5a inhibited MV4‐11 cells with IC₅₀ of 4.3 µM at 72 h while it was 8.7 µM in THP‐1 cells, thus showing two‐fold selective inhibition against the oncogenic ITD mutation. The ability of 5a to modulate cell death was examined. High‐throughput protein profiling revealed low levels of the growth factors IGFBP‐2 and ‐4 with the blockage of various apoptotic inhibitors such as Survivin. p21 with cellular stress mechanisms was characterized by increased expression of HSP proteins along with TNF‐β. Mechanistically, compounds 5a and 5b inhibited FLT3 kinase with IC₅₀ values of 2.49 and 1.45 µM, respectively. Theoretical docking studies supported the compounds' ability to bind to the FLT3 ATP binding site with the formation of highly stable complexes as evidenced by molecular dynamics simulations. The designed compounds also provide suitable drug candidates with no violation of drug likeability rules.

Curcumin is one of the most researched phytochemicals by pharmacologists and formulation scientists to unleash its potential therapeutic benefits and tackle inherent biopharmaceutic problems. In this study, the native β-cyclodextrin (CD) and three derivatives, namely, Captisol (sulfobutyl ether β-CD), hydroxypropyl β-cyclodextrin, and hydroxyethyl β-cyclodextrin were investigated for inclusion complexes with curcumin using two preparation methods (physical mixing and solvent evaporation). The prepared complexes were studied for docking, solubility, FTIR, DSC, XRD, and dissolution rates. The best-fitting curcumin: cyclodextrins (the latter of the two CDs) were evaluated for cytotoxicity using human breast cell lines (MCF-7). Dose-dependent cytotoxicity was recorded as IC50% for curcumin, curcumin: hydroxyethyl β-cyclodextrin, and curcumin: hydroxypropyl β-cyclodextrin were 7.33, 7.28, and 19.05 µg/mL, respectively. These research findings indicate a protective role for the curcumin: hydroxypropyl β-cyclodextrin complex on the direct cell lines of MCF-7.

Proteases and RNA-Dependent RNA polymerase, major enzymes which are essential targets involved in the life and replication of SARS-CoV-2. This study aims at in silico examination of the potential ability of coumarins and their derivatives to inhibit the replication of SARS-Cov-2 through multiple targets, including the main protease, papain-like protease and RNA-Dependent RNA polymerase. Several coumarins as biologically active compounds were studied, including coumarin antibiotics and some naturally reported antiviral coumarins. Aminocoumarin antibiotics, especially coumermycin, showed a high potential to bind to the enzymes’ active site, causing possible inhibition and termination of viral life. They demonstrate the ability to bind to residues essential for triggering the crucial cascades within the viral cell. Molecular dynamics simulations for 50 ns supported these data pointing out the formation of rigid, stable Coumermycin/enzyme complexes. These findings strongly suggest the possible use of Coumermycin, Clorobiocin or Novobiocin in the fight against COVID-19, but biological evidence is still required to support such suggestions.