Novel sulfonamide derivatives as multitarget antidiabetic agents: design, synthesis, and biological evaluation.

A series of new sulfonamide derivatives connected through an imine linker to five or seven membered heterocycles were designed and synthesized. All synthesized derivatives were characterized using a variety of spectroscopic methods, including IR, 1HNMR, and 13CNMR. In vitro α-glucosidase and α-amylase inhibition activities, as well as glucose uptake were assessed for each of the synthesized compounds. Four sulfonamide derivatives namely 3a, 3b, 3h and 6 showed excellent inhibitory potential against α-glucosidase with IC50 values of 19.39, 25.12, 25.57 and 22.02 µM, respectively. They were 1.05- to 1.39-fold more potent than acarbose. Sulfonamide derivatives 3g, 3i and 7 (EC50 values of 1.29, 21.38 and 19.03 µM, respectively) exhibited significant glucose uptake activity that were 1.62- to 27-fold more potent than berberine. Both α-glucosidase protein (PDB: 2QMJ) and α-amylase (PDB: 1XCW) complexed with acarbose were adopted for docking investigations for the most active synthesized compounds. The docked compounds were able to inhabit the same space as the acarviosin ring of acarbose. The docking of the most active compounds showed an analogous binding with the active site of α-glucosidase as acarbose. The superior activity of the synthesized compounds against α-glucosidase enzyme than α-amylase enzyme can be rationalized by the weak interaction with the α-amylase. The physiochemical parameters of all synthesized compounds were aligned with Lipinski's rule of five.

Challenging the anticolorectal cancer capacity of quinoxaline-based scaffold via triazole ligation unveiled new efficient dual VEGFR-2/MAO-B inhibitors.

Monoamine oxidases (MAOs) and vascular endothelial growth factor receptor-2 (VEGFR-2) are promoters of colorectal cancer (CRC) and central signaling nodes in epithelial-mesenchymal transition (EMT) induced by activating hypoxia-inducible factors (HIFs). Herein, a novel series of rationally designed triazole-tethered quinoxalines were synthesized and evaluated against HCT-116 CRC cells. The tailored scaffolds combine the pharmacophoric themes of both VEGFR-2 inhibitors and MAO inhibitors. All the synthesized derivatives were screened utilizing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay for their possible cytotoxic effects on normal human colonocytes, then evaluated for their anticancer activities against HCT-116 cells overexpressing MAOs. The hit derivatives 11 and 14 exhibited IC50 = 18.04 and 7.850 µM, respectively, against HCT-116cells within their EC100 doses on normal human colonocytes. Wound healing assay revealed their efficient CRC antimetastatic activities recording HCT-116 cell migration inhibition exceeding 75 %. In vitro enzymatic assays demonstrated that both 11 and 14 efficiently inhibited VEGFR-2 (IC50 = 88.79 and 9.910 nM), MAO-A (IC50 = 0.763 and 629.1 nM) and MAO-B (IC50 = 0.488 and 209.6 nM) with observed MAO-B over MAO-A selectivity (SI = 1.546 and 3.001), respectively. Enzyme kinetics studies were performed for both compounds to identify their mode of MAO-B inhibition. Furthermore, qRT-PCR analysis showed that the hits efficiently downregulated HIF-1α in HCT-116cells by 3.420 and 16.96 folds relative to untreated cells. Docking studies simulated their possible binding modes within the active sites of VEGFR-2 and MAO-B to highlight their essential structural determinants of activities. Finally, they recorded in silico drug-like absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles as well as ligand efficiency metrics.

Reinvestigation of Passerini and Ugi scaffolds as multistep apoptotic inducers via dual modulation of caspase 3/7 and P53-MDM2 signaling for halting breast cancer.

Selective induction of breast cancer apoptosis is viewed as the mainstay of various ongoing oncology drug discovery programs. Passerini scaffolds have been recently exploited as selective apoptosis inducers via a caspase 3/7 dependent pathway. Herein, the optimized Passerini caspase activators were manipulated to synergistically induce P53-dependent apoptosis via modulating the closely related P53-MDM2 signaling axis. The adopted design rationale and synthetic routes relied on mimicking the general thematic features of lead MDM2 inhibitors incorporating multiple aromatic rings. Accordingly, the cyclization of representative Passerini derivatives and related Ugi compounds into the corresponding diphenylimidazolidine and spiro derivative was performed, resembling the nutlin-based and spiro MDM-2 inhibitors, respectively. The study was also extended to explore the apoptotic induction capacity of the scaffold after simplification and modifications. MTT assay on MCF-7 and MDA-MB231 breast cancer cells compared to normal fibroblasts (WI-38) revealed their promising cytotoxic activities. The flexible Ugi derivatives 3 and 4, cyclic analog 8, Passerini adduct 12, and the thiosemicarbazide derivative 17 were identified as the study hits regarding cytotoxic potency and selectivity, being over 10-folds more potent (IC50 = 0.065-0.096 µM) and safer (SI = 4.4-18.7) than doxorubicin (IC50 = 0.478 µM, SI = 0.569) on MCF-7 cells. They promoted apoptosis induction via caspase 3/7 activation (3.1-4.1 folds) and P53 induction (up to 4 folds). Further apoptosis studies revealed that these compounds enhanced gene expression of BAX by 2 folds and suppressed Bcl-2 expression by 4.29-7.75 folds in the treated MCF-7 cells. Docking simulations displayed their plausible binding modes with the molecular targets and highlighted their structural determinants of activities for further optimization studies. Finally, in silico prediction of the entire library was computationally performed, showing that most of them could be envisioned as drug-like candidates.

Repurposing 1,2,4-oxadiazoles as SARS-CoV-2 PLpro inhibitors and investigation of their possible viral entry blockade potential.

Although vaccines are obviously mitigating the COVID-19 pandemic diffusion, efficient complementary antiviral agents are urgently needed to combat SARS-CoV-2. The viral papain-like protease (PLpro) is a promising therapeutic target being one of only two essential proteases crucial for viral replication. Nevertheless, it dysregulates the host immune sensing response. Here we report repositioning of the privileged 1,2,4-oxadiazole scaffold as promising SARS-CoV-2 PLpro inhibitor with potential viral entry inhibition profile. The design strategy relied on mimicking the general structural features of the lead benzamide PLpro inhibitor GRL0617 with isosteric replacement of its pharmacophoric amide backbone by 1,2,4-oxadiazole core. Inspired by the multitarget antiviral agents, the substitution pattern was rationalized to tune the scaffold's potency against other additional viral targets, especially the spike receptor binding domain (RBD) that is responsible for the viral invasion. The Adopted facial synthetic protocol allowed easy access to various rationally substituted derivatives. Among the evaluated series, the 2-[5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl]aniline (5) displayed the most balanced dual inhibitory potential against SARS-CoV-2 PLpro (IC50=7.197 µM) and spike protein RBD (IC50 = 8.673 µM), with acceptable ligand efficiency metrics, practical LogP (3.8) and safety profile on Wi-38 (CC50 = 51.78 µM) and LT-A549 (CC50 = 45.77 µM) lung cells. Docking simulations declared the possible structural determinants of activities and enriched the SAR data for further optimization studies.

4-(N-Phthalimido)phenyl Isonitrile as a Novel Convertible Isocyanide Analogue with the Odorless Property as an Extra Bonus.

We explored a new isonitrile, namely 4-(N-phthalimido)phenyl isonitrile, with extraordinary features. The novel isocyanide has a pharmacophore, the phthalimido (Pht) group, that possesses promising pharmaceutical activities. We found that the novel isonitrile is unexpectedly odorless as an extra bonus which makes its handling easy in organic synthesis to serve as a scaffold for building several new amide derivatives through multicomponent reactions, overcoming the stink of common aromatic isonitriles such as phenyl isonitrile, benzyl isonitrile, p-nitrophenyl isonitrile, and ethyl 4-isocyano benzoate. The novel isonitrile 9 serves as a source of N-protected isonitrile with a Pht group, where the Pht group can be easily removed via hydrazinolysis, affording the corresponding primary amine/alcohol scaffold which could be used as a precursor to synthesize Passerini products via acylation directly to afford Passerini adducts 14 and 15 without carrying out the traditional Passerini three-component reaction; this new isonitrile is considered as a novel convertible isocyanide analogue.

Nature-inspired new isoindole-based Passerini adducts as efficient tumor-selective apoptotic inducers via caspase-3/7 activation.

The development of novel therapeutics promoting selective tumor elimination is the mainstay of clinical oncology. Emerging insights into tumor targeting reveal caspases activation, especially caspase-3, as a personalized anticancer strategy. Our on-going cancer research has exploited Passerini α-acyloxy carboxamides as caspase-3/7-dependent apoptotic inducers. Herein, we adopted scaffold hopping design to introduce new series of isoindole-based Passerini adducts as caspase-3/7 activators inspired by natural alkaloids from Lion's Mane mushroom promoting caspase-3-mediated apoptosis. Additional pharmacophoric motifs of lead caspase activators were merged into the tailored Passerini skeleton. The rationally designed adducts were synthesized utilizing one-pot reaction of the novel 4-(2'-phthalimido)phenylisonitrile 5, cyclohexanone and miscellaneous carboxylic acids under Passerini conditions. All derivatives were screened for their antiproliferative activities against lung A549, colorectal Caco-2 and breast MDA-MB 231 cancer cells compared to normal fibroblasts utilizing MTT assay. Most of the evaluated derivatives were superior to 5-fluorouracil. The 2-(1H-indol-3-yl)acetate derivative (8a) recorded the highest anticancer potency (IC50 = 0.04-0.11 µM) and selectivity (SI = 42.59-125.53), followed by the 3-(4-(trifluoromethyl)phenyl)acrylate (8m), the 2-(phenylsulfonyl)glycinate (8q), and the 2-(2-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)acetate (8c) derivatives, respectively. The four hits induced cancer cells apoptosis (up to 57.99%) via caspase-3/7 activation (up to 5.47 folds). Apoptosis-inducing factor1 (AIF1) quantification assay excluded their caspase-independent apoptosis induction potential via AIF1 signaling pathway. Docking simulations clarified the possible binding modes of the hit compounds with XIAP BIR2 domain; the specific receptor of caspase-3/7 activators, and aided identifying their structural determinants of activity. Finally, their practical LogP, efficiency metrics, in silico ADMET profiling were drug-like.

Structure optimization of new tumor-selective Passerini α-acyloxy carboxamides as Caspase-3/7 activators.

Selective elimination of tumors has always been the mainstay of oncology research. The on-going research underlying the cellular apoptotic mechanisms reveal caspases activation, especially the key effector caspase-3, as a personalized tumor-selective therapeutic strategy. Our continued research protocol has exploited new optimized Passerini α-acyloxy carboxamides as efficient apoptotic inducers via caspase-3/7 dependent mechanism with highly selective anticancer profiles. The adopted design rationale relied on excluding structural alerts of previous leads, while merging various pharmacophoric motifs of natural and synthetic caspase activators via optimized one-pot Passerini reaction conditions. The prepared compounds resulting from Passerini reaction were screened for their cytotoxic activities against colorectal Caco-2 and liver HepG-2 cancer cells compared to normal fibroblasts utilizing MTT assay. Notably, all compounds exhibited promising low-range submicromolar IC50 against the studied cancer cell lines, with outstanding tumor selectivity (SI values up to 266). Hence, they were superior to 5-fluorouracil. Notably, 7a, 7g, and 7j conferred the highest potencies against Caco-2 and HepG-2 cells and were selected for further mechanistic studies. Caspas-3/7 activation assay of the hit compounds and flow cytometric analysis of the treated apoptotic cancer cells demonstrated their significant caspase activation potential (up to 4.2 folds) and apoptotic induction capacities (up to 58.7%). Further assessment of Bcl2 expression was performed being a physiological caspase-3 substrate. Herein, the three studied Passerini adducts were able to downregulate Bcl2 in the treated Caco-2 cells. Importantly, the mechanistic studies results of the three hits echoed their preliminary MTT antiproliferative potencies data highlighting their caspase-3 dependent apoptotic induction. Finally, the in silico predicted physicochemical and pharmacokinetic profiles, as well as ligand efficiency metrics were drug-like.

Synthesis of a new magnetic Sulfacetamide-Ethylacetoacetate hydrazone-chitosan Schiff-base for Cr(VI) removal.

In this study, a novel magnetic organic-inorganic composite was fabricated. Chitosan, sulfacetamide and ethylacetoacetae were used to prepare a new Sulfacetamide-Ethylacetoacetate hydrazone-chitosan Schiff-base (SEH-CSB) with a variety of active sites that capable of forming coordinate covalent bonds with Cr(VI). This was followed by modification of the formed SHE-CSB with NiFe2O4 to obtain the magnetic Chitosan-Schiff-base composite (NiFe2O4@SEH-CSB). NiFe2O4@SEH-CSB was characterized using FTIR, zeta potential, SEM, VSM and XPS. Results clarified that SHE played a crucial role in the removal of Cr(VI). The removal of Cr(VI) on NiFe2O4@SEH-CSB was found to be more fitted to pseudo-second order kinetics model and Freundlich isotherm. Besides, the maximum adsorption capacity of NiFe2O4@SEH-CSB towards Cr(VI) was found to be 373.61 mg/g. The plausible mechanism for the removal of Cr(VI) by NiFe2O4@SEH-CSB composite suggested the domination of coulombic interaction, outer-sphere complexation, ion-exchange, surface complexation and coordinate-covalent bond pathways. The magnetic property enabled easy recycling of NiFe2O4@SEH-CSB composite for seven sequential cycles.

Exploration of Nitroaromatic Antibiotics via Sanger's Reagent: Synthesis, In Silico, and Antimicrobial Evaluation.

Facile synthesis of molecular hybrids containing a 2,4-dinitrophenyl moiety was achieved via nucleophilic aromatic substitution of the fluoride anion of Sanger's reagent (2,4-dinitrofluorobenzene) with various N, S, and O nucleophiles, considered as bioactive moieties. Antimicrobial evaluation of the new hybrids was carried out using amoxicillin and nystatin as antibacterial and antifungal reference standards, respectively. MIC test results identified the compounds 3, 4, and 7 as the most active hybrids against standard strains and multidrug-resistant strains (MDR) of Staphylococcus aureus, Escherichia coli, and Pseudomonas aurginosa. Most of the hybrids displayed two times the antibacterial activity of AMOX against MDR Pseudomonas aeruginosa, E. coli, and a standard strain of P. aeruginosa (ATCC 29853), while demonstrating a weak antifungal profile against Candida albicans. Selectivity profiles of the promising compounds 3, 4, 6, 7, 8, and 11 on WI-38 human cells were characterized, which indicated that compound 3 is the safest one (CC50 343.72 µM). The preferential anti-Gram-negative activity of our compounds led us to do docking studies on DNA gyrase B. Docking revealed that the potential antimicrobial compounds fit well into the active site of DNA gyrase B. Furthermore, in silico absorption, distribution, metabolism, and excretion (ADME) predictions revealed that most of the new compounds have high gastrointestinal absorption and a good oral bioavailability with no BBB permeability.

Beyond direct Nrf2 activation; reinvestigating 1,2,4-oxadiazole scaffold as a master key unlocking the antioxidant cellular machinery for cancer therapy.

Harnessing the antioxidant cellular machinery has sparked considerable interest as an efficient anticancer strategy. Activating Nrf2, the master switch of the cellular redox system, suppresses ROS, alleviates oxidative stress, and halts cancer progression. 1,2,4-oxadiazoles are iconic direct Nrf2 activators that disrupt Nrf2 interaction with its endogenous repressor Keap1. This study introduces rationally designed 1,2,4-oxadiazole derivatives that inhibit other Nrf2 suppressors (TrxR1, IKKα, and NF-kB) thus enhancing Nrf2 activation for preventing oxidative stress and carcinogenesis. Preliminary screening showed that the phenolic oxadiazoles 11, 15, and 19 were comparable to ascorbic acid (ROS scavenging) and EDTA (iron chelation), and superior to doxorubicin against HepG-2, MDA-MB231, and Caco-2 cells. They suppressed ROS by 3 folds and activated Nrf2 by 2 folds in HepG-2 cells. Mechanistically, they inhibited TrxR1 (IC50; 13.19, 17.89, and 9.21 nM) and IKKα (IC50; 11.0, 15.94, and 19.58 nM), and downregulated NF-κB (7.6, 1.4 and 1.9 folds in HepG-2), respectively. They inhibited NADPH oxidase (IC50; 16.4, 21.94, and 10.71 nM, respectively) that potentiates their antioxidant activities. Docking studies predicted their important structural features. Finally, they recorded drug-like in silico physicochemical properties, ADMET, and ligand efficiency metrics.

Two decades of recent advances of Ugi reactions: synthetic and pharmaceutical applications.

Multicomponent reactions (MCRs) are powerful synthetic tools in which more than two starting materials couple with each other to form multi-functionalized compounds in a one-pot process, the so-called "tandem", "domino" or "cascade" reaction, or utilizing an additional step without changing the solvent, the so-called a sequential-addition procedure, to limit the number of synthetic steps, while increasing the complexity and the molecular diversity, which are highly step-economical reactions. The Ugi reaction, one of the most common multicomponent reactions, has recently fascinated chemists with the high diversity brought by its four- or three-component-based isonitrile. The Ugi reaction has been introduced in organic synthesis as a novel, efficient and useful tool for the preparation of libraries of multifunctional peptides, natural products, and heterocyclic compounds with stereochemistry control. In this review, we highlight the recent advances of the Ugi reaction in the last two decades from 2000-2019, mainly in the synthesis of linear or cyclic peptides, heterocyclic compounds with versatile ring sizes, and natural products, as well as the enantioselective Ugi reactions. Meanwhile, the applications of these compounds in pharmaceutical trials are also discussed.

Battle tactics against MMP-9; discovery of novel non-hydroxamate MMP-9 inhibitors endowed with PI3K/AKT signaling attenuation and caspase 3/7 activation via Ugi bis-amide synthesis.

Matrix metalloproteinases (MMPs) are major modulators of the tumor microenvironment. They participate in extracellular matrix turnover, tumor growth, angiogenesis and metastasis. Accordingly, MMPs inhibition seems to be ideal solution to control cancer. Many MMPs inhibitors have been introduced ranging from hydroxamate-based peptidomimetics to the next generation non-hydroxamate inhibitors. Among MMPs, MMP-9 is attractive druggable anticancer target. Studies showed that inhibiting AKT, the central signaling node of MMP-9 upregulation, provides additional MMP-9 blockade. Furthermore, caspase-dependent AKT cleavage leads to cell death. Herein, Ugi MCR was utilized as a rapid combinatorial approach to generate various decorated bis-amide scaffolds as dual MMP-9/AKT inhibitors endowed with caspase 3/7 activation potential. The target adducts were designed to mimic the thematic structural features of non-hydroxamate MMP inhibitors. p-Nitrophenyl isonitrile 1 was utilized as structure entry to Ugi products with some structural similarities to amide-based caspase 3/7 activators. Besides, various acids, amines and aldehydes were employed as Ugi educts to enrich the SAR data. All adducts were screened for cytotoxicity against normal fibroblasts and three cancer cell lines; MCF-7, NFS-60 and HepG-2 utilizing MTT assay. 8, 11 and 28 were more active and safer than doxorubicin with single-digit nM IC50 and promising selectivity. Mechanistically, they exhibited dual MMP-9/AKT inhibition at single-digit nM IC50 with excellent selectivity over MMP-1,-2 and -13, and induced >51% caspase 3/7 activation. Consequently, they induced >49% apoptosis as detected by flow cytometric analysis, and inhibited cell migration (metastasis) up to 97% in cancer cells. Docking simulations were nearly consistent with enzymatic evaluation, also declared possible binding modes and essential structure features of active compounds. In silico physicochemical properties, ligand efficiency and drug-likeness metrics were reasonable for all adducts. Interestingly, 8 and 28 can be considered as drug-like candidates.

Design, synthesis and biological evaluation of novel α-acyloxy carboxamides via Passerini reaction as caspase 3/7 activators.

Evasion of apoptosis is a hallmark of cancer. Caspases; the key executors of apoptotic cascade are attractive targets for selective induction of apoptosis in cancer cells. Within this approach, various caspase activators were introduced as lead anticancer agents. In the current study, a new series of multifunctional Passerini products was synthesized and evaluated as potent caspase-dependent apoptotic inducers. The synthetic strategy adopted this isocyanide-based multicomponent reaction to possibly mimic the pharmacophoric features of various lead apoptotic inducers, where a series of α-acyloxy carboxamides was prepared from p-nitrophenyl isonitrile, cyclohexanone and various carboxylic acids. Accordingly, the main amide-based scaffold was decorated by substituents with varying nature and size to gain more information about structure-activity relationship. All the synthesized compounds were screened for cytotoxicity against normal human fibroblasts and their potential anticancer activities against three human cancer cell lines; MCF-7 (breast), NFS-60 (myeloid leukemia), and HepG-2 (liver) utilizing MTT assay. Among the most active compounds, 13, 21 and 22 were more potent and safer than doxorubicin with nanomolar IC50 values and promising selectivity indices. Mechanistically, 13, 21 and 22 induced apoptosis by significant caspase activation in all the screened cancer cell lines utilizing flow cytometric analysis and caspase 3/7 activation assay. Again, 13 and 21 recorded higher activation percentages than doxorubicin, while 22 showed comparable results. Apoptosis-inducing factor1 (AIF1) quantification assay declared that 13, 21 and 22 didn't mediate apoptosis through AIF1-dependent pathway (i.e. only by caspase activation). Physicochemical properties, pharmacokinetic profiles, ligand efficiency metrics and drug-likeness data of all the synthesized compounds were computationally predicted and showed that 13, 21 and 22 could be considered as drug-like candidates. Finally, selected compounds were preliminarily screened for possible antimicrobial activities searching for dual anticancer/antimicrobial agents as an advantageous approach for cancer therapy.

Regioselectivity in the glycosylation of 5-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole-3-thiol.

The glycosylation of 5-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole-3-thiol (1) and its 3-benzylsulfanyl and 3-methylsulfanyl derivatives with different glycosyl halides 2-4 has been studied in presence of base. The S-glycosides 5-7 were obtained in the presence of triethylamine, whereas the respective S,N(4)-bis(glycosyl) derivatives 8-10 were synthesized in the presence of potassium carbonate; the S,N(2)-bis(glycosyl) isomer 11 could also be isolated in the case of the galactosyl analog. Similarly, after protecting 1 as 3-benzyl(methyl)sulfanyl derivatives 12 or 13, the N(4)-glycosyl analogs 14-19 as well as minor amounts of S,N(2)-bis(galactosyl) isomers 20 and 21 were formed. The theoretical calculations using AM1 semiempirical methods agreed with the experimental results. Microwave irradiation (MWI) led to higher yields in much less time than the conventional methods, and no change in regioselectivity has been noticed.