Microwave‐Assisted Syntheses of Benzimidazole‐Containing Selenadiazole Derivatives That Induce Cell‐Cycle Arrest and Apoptosis in Human Breast Cancer Cells by Activation of the ROS/AKT Pathway

The use of selenium‐containing heterocyclic compounds as potent cancer chemopreventive and chemotherapeutic agents has been well documented by a large number of clinical studies. In this study we developed a new approach to synthesize four benzimidazole‐containing selenadiazole derivatives (BSeDs). The method uses a combination of peptide coupling reagents and microwave irradiation. This strategy features milder reaction conditions, higher yields, and shorter reaction times. The synthetic BSeDs were identified as potent antiproliferative agents against the human MCF‐7 and MDA‐MB‐231 breast cancer cell lines. Compounds 1 b (5‐(6‐methyl‐1H‐benzo[d]imidazol‐2‐yl)benzo[c][1,2,5]selenadiazole), 1 c (5‐(6‐chloro‐1H‐benzo[d]imidazol‐2‐yl)benzo[c][1,2,5]selenadiazole), and 1 d (5‐(6‐bromo‐1H‐benzo[d]imidazol‐2‐yl)benzo[c][1,2,5]selenadiazole) were found to show greater cytotoxicity against the triple‐negative breast cancer cell line MDA‐MB‐231 than MCF‐7, and to exhibit dose‐dependent inhibition of cell migration, in which a significant decrease in the zone of cell monolayer wound closure was observed relative to untreated controls. Our results demonstrate that BSeDs can cause cell‐cycle arrest and apoptosis in MDA‐MB‐231 cells by inducing DNA damage, inhibiting protein kinase B (AKT), and activating mitogen‐activated protein kinase (MAPK) family members through the overproduction of reactive oxygen species (ROS). Taken together, the results of this study provide a facile microwave‐assisted strategy for the synthesis of selenium‐containing organic compounds that exhibit a high level of anticancer efficacy.     

LEGO‐Inspired Drug Design: Unveiling a Class of Benzo[d]thiazoles Containing a 3,4‐Dihydroxyphenyl Moiety as Plasma Membrane H+‐ATPase Inhibitors

The fungal plasma membrane H⁺‐ATPase (Pma1p) is a potential target for the discovery of new antifungal agents. Surprisingly, no structure–activity relationship studies for small molecules targeting Pma1p have been reported. Herein, we disclose a LEGO‐inspired fragment assembly strategy for the design, synthesis, and discovery of benzo[d]thiazoles containing a 3,4‐dihydroxyphenyl moiety as potential Pma1p inhibitors. A series of 2‐(benzo[d]thiazol‐2‐ylthio)‐1‐(3,4‐dihydroxyphenyl)ethanones was found to inhibit Pma1p, with the most potent IC₅₀ value of 8 μm in an in vitro plasma membrane H⁺‐ATPase assay. These compounds were also found to strongly inhibit the action of proton pumping when Pma1p was reconstituted into liposomes. 1‐(3,4‐Dihydroxyphenyl)‐2‐((6‐(trifluoromethyl)benzo[d]thiazol‐2‐yl)thio)ethan‐1‐one (compound 38 ) showed inhibitory activities on the growth of Candida albicans and Saccharomyces cerevisiae, which could be correlated and substantiated with the ability to inhibit Pma1p in vitro.     

Evaluating p97 Inhibitor Analogues for Potency against p97–p37 and p97–Npl4–Ufd1 Complexes

We previously found that the p97 cofactor, p47, significantly decreased the potency of some ATP‐competitive p97 inhibitors such as ML240 [2‐(2‐amino‐1H‐benzo[d]imidazol‐1‐yl)‐N‐benzyl‐8‐methoxyquinazolin‐4‐amine] and ML241 [2‐(2H‐benzo[b][1,4]oxazin‐4(3H)‐yl)‐N‐benzyl‐5,6,7,8 tetrahydroquinazolin‐4‐amine]. In this study, we aimed to evaluate inhibitor potencies against two additional p97 cofactor complexes, p97–p37 and p97–Npl4–Ufd1. We focused on these two cofactor complexes, because the protein sequence of p37 is 50 % identical to that of p47, and the Npl4–Ufd1 heterodimer (NU) is the most‐studied p97 cofactor complex. We screened 200 p97 inhibitor analogues for their ability to inhibit the ATPase activity of p97 alone and of p97–p37 and p97–NU complexes. In contrast to the effect of p47, p37 and NU did not significantly change the potencies of most of the compounds. These results highlight differences among p97 cofactors in influencing p97 conformation and effects of inhibitors on p97 complexes, as compared to p97 alone. Continued efforts are needed to advance the development of complex‐specific p97 inhibitors.     

Evaluating p97 Inhibitor Analogues for Their Domain Selectivity and Potency against the p97–p47 Complex

We previously found that p97 ATPase inhibitors 2‐(2‐amino‐1H‐benzo[d]imidazol‐1‐yl)‐N‐benzyl‐8‐methoxyquinazolin‐4‐amine ( ML240 ) and 2‐(2H‐benzo[b][1,4]oxazin‐4(3H)‐yl)‐N‐benzyl‐5,6,7,8‐tetrahydroquinazolin‐4‐amine ( ML241 ) specifically target the D2 domain of wild‐type p97. In addition, one of the major p97 cofactors, p47, decreases their potencies by ～50‐fold. In contrast, N²,N⁴‐dibenzylquinazoline‐2,4‐diamine ( DBeQ ) targets both the D1 and D2 domains and shows only a four‐ to sixfold decrease in potency against the p97–p47 complex. To elucidate structure–activity relationships for the inhibitors, we screened 200 p97 inhibitor analogues for their ability to inhibit the ATPase activity of either or both of the D1 or D2 domains, as well for their effects on p47 potency. The selectivity of 29 of these compounds was further examined by eight‐dose titrations. Four compounds showed modest selectivity for inhibiting the ATPase activity of D1. Eleven compounds inhibited D2 with greater potencies, and four showed similar potencies against D1 and D2. p47 decreased the potencies of the majority of the compounds and increased the potencies of five compounds. These results highlight the possibility of developing domain‐selective and complex‐specific p97 inhibitors in order to further elucidate the physiological roles of p97 and its cofactors.     

Experimental and Computational Evaluation of Piperonylic Acid Derived Hydrazones Bearing Isatin Moieties as Dual Inhibitors of Cholinesterases and Monoamine Oxidases

A set of piperonylic acid derived hydrazones with variable isatin moieties was synthesized and evaluated for their inhibitory activity against the enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidases A and B (MAO-A/B). The results of in vitro studies revealed IC₅₀ values in the micromolar range, with the majority of the compounds showing selectivity for the MAO-B isoform. N-[2-Oxo-1-(prop-2-ynyl)indolin-3-ylidene]benzo[d][1,3]dioxole-5-carbohydrazide ( 3 ) was identified as a lead AChE inhibitor with IC₅₀=0.052±0.006 μm . N-[(3E)-5-chloro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]-2H-1,3-benzodioxole-5-carbohydrazide ( 2 ) was the lead MAO-B inhibitor with IC₅₀=0.034±0.007 μm , and showed 50 times greater selectivity for MAO-B over MAO-A. The kinetic studies revealed that compounds 2 and 3 displayed competitive and reversible inhibition of AChE and MAO-B, respectively. The molecular docking studies revealed the significance of hydrophobic interactions in the active site pocket of the enzymes under investigation. Further optimization studies might lead to the development of potential neurotherapeutic agents.     

Efficient Inhibition of Telomerase by Nickel–Salophen Complexes

Four nickel(II)–salophen complexes containing alkyl‐imidazolium chains connected at the ortho or meta positions were prepared: N,N′‐bis(2‐hydroxy‐4‐methyl‐3H‐imidazol‐1‐iumbenzylideneamino)phenylenediamine ( 1 ), N,N′‐bis(2‐hydroxy‐3‐methyl‐3H‐imidazol‐1‐iumbenzylideneamino)phenylenediamine ( 2 ), N,N′‐bis(2‐hydroxy‐3‐methyl‐3H‐imidazol‐1‐iumbenzylideneamino)methyl‐3H‐imidazol‐1‐iumphenylenediamine ( 3 ), and N,N′‐bis(2‐hydroxy‐4‐methyl‐3H‐imidazol‐1‐iumbenzylideneamino)methyl‐3H‐imidazol‐1‐iumphenylenediamine ( 4 ). They protect G‐quadruplex DNA (G₄‐DNA) against thermal denaturation and show K_A values in the range of 7.4×10⁵ to 4×10⁷ m ^?1 for G₄‐DNA models. Complex 4 exhibits an IC₅₀ value of 70 nm for telomerase inhibition.     

Designing Dual Transglutaminase 2/Histone Deacetylase Inhibitors Effective at Halting Neuronal Death

In recent years there has been a clear consensus that neurodegenerative conditions can be better treated through concurrent modulation of different targets. Herein we report that combined inhibition of transglutaminase 2 (TG2) and histone deacetylases (HDACs) synergistically protects against toxic stimuli mediated by glutamate. Based on these findings, we designed and synthesized a series of novel dual TG2–HDAC binding agents. Compound 3 [(E)‐N‐hydroxy‐5‐(3‐(4‐(3‐oxo‐3‐(pyridin‐3‐yl)prop‐1‐en‐1‐yl)phenyl)thioureido)pentanamide] emerged as the most interesting of the series, being able to inhibit TG2 and HDACs both in vitro (TG2 IC₅₀=13.3±1.5 μm , HDAC1 IC₅₀=3.38±0.14 μm , HDAC6 IC₅₀=4.10±0.13 μm ) and in cell‐based assays. Furthermore, compound 3 does not exert any toxic effects in cortical neurons up to 50 μm and protects neurons against toxic insults induced by glutamate (5 mm ) with an EC₅₀ value of 3.7±0.5 μm .     

Discovery and Characterization of CD12681, a Potent RORγ Inverse Agonist,Preclinical Candidate for the Topical Treatment of Psoriasis

With possible implications in multiple autoimmune diseases, the retinoic acid receptor‐related orphan receptor RORγ has become a sought‐after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated in the discovery of N‐(2,4‐dimethylphenyl)‐N‐isobutyl‐2‐oxo‐1‐[(tetrahydro‐2H‐pyran‐4‐yl)methyl]‐2,3‐dihydro‐1H‐benzo[d]imidazole‐5‐sulfonamide (CD12681), a potent inverse agonist with in vivo activity in an IL‐23‐induced mouse skin inflammation model.     

Synthesis,Biological Activity,and Mechanism of Action of 2‐Pyrazyl and Pyridylhydrazone Derivatives,New Classes of Antileishmanial Agents

In this work, we report the antileishmanial activity of 23 compounds based on 2‐pyrazyl and 2‐pyridylhydrazone derivatives. The compounds were tested against the promastigotes of Leishmania amazonensis and L. braziliensis, murine macrophages, and intracellular L. amazonensis amastigotes. The most potent antileishmanial compound was selected for investigation into its mechanism of action. Among the evaluated compounds, five derivatives [(E)‐3‐((2‐(pyridin‐2‐yl)hydrazono)methyl)benzene‐1,2‐diol ( 2 b ), (E)‐4‐((2‐(pyridin‐2‐yl)hydrazono)methyl)benzene‐1,3‐diol ( 2 c ), (E)‐4‐nitro‐2‐((2‐(pyrazin‐2‐yl)hydrazono)methyl)phenol ( 2 s ), (E)‐2‐(2‐(pyridin‐2‐ylmethylene)hydrazinyl)pyrazine ( 2 u ), and (E)‐2‐(2‐((5‐nitrofuran‐2‐yl)methylene)hydrazinyl)pyrazine ( 2 v )] exhibited significant activity against L. amazonensis amastigote forms, with IC₅₀ values below 20 μm . The majority of the compounds did not show any toxic effect on murine macrophages. Preliminary studies on the mode of action of members of this hydrazine‐derived series indicate that the accumulation of reactive oxygen species (ROS) and disruption of parasite mitochondrial function are important for the pharmacological effect on L. amazonensis promastigotes.     

The Discovery of Potent Nonstructural Protein 5A (NS5A) Inhibitors with a Unique Resistance Profile—Part 1

Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol–Myers–Squibb, is a potent NS5A inhibitor currently under investigation in phase 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl‐imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)‐1‐((S)‐2‐(4‐(4‐(6‐(2‐((S)‐1‐((methoxycarbonyl)‐L ‐valyl)pyrrolidin‐2‐yl)‐1H‐imidazol‐5‐yl)quinoxalin‐2‐yl)phenyl)‐1H‐imidazol‐2‐yl)pyrrolidin‐1‐yl)‐3‐methyl‐1‐oxobutan‐2‐yl)carbamate ( 17 ), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half‐life. This compound represents a promising lead that warrants further evaluation.     

Discovery of a Nanomolar Multikinase Inhibitor (KST016366): A New Benzothiazole Derivative with Remarkable Broad‐Spectrum Antiproliferative Activity

Herein we report the discovery of compound 6 [KST016366; 4‐((2‐(3‐(4‐((4‐ethylpiperazin‐1‐yl)methyl)‐3‐(trifluoromethyl)phenyl)ureido)benzo[d]thiazol‐6‐yl)oxy)picolinamide] as a new potent multikinase inhibitor through minor structural modification of our previously reported RAF kinase inhibitor A . In vitro anticancer evaluation of 6 showed substantial broad‐spectrum antiproliferative activity against 60 human cancer cell lines. In particular, it showed GI₅₀ values of 51.4 and 19 nm against leukemia K‐562 and colon carcinoma KM12 cell lines, respectively. Kinase screening of compound 6 revealed its nanomolar‐level inhibitory activity of certain oncogenic kinases implicated in both tumorigenesis and angiogenesis. Interestingly, 6 displays IC₅₀ values of 0.82, 3.81, and 53 nm toward Tie2, TrkA, and ABL‐1 (wild‐type and T315I mutant) kinases, respectively. Moreover, 6 is orally bioavailable with a favorable in vivo pharmacokinetic profile. Compound 6 may serve as a promising candidate for further development of potent anticancer chemotherapeutics.     

New Ruthenium Catalysts for Asymmetric Transfer Hydrogenation of Prochiral Ketones

Tridentate N,N,N‐pyridinebisimidazolines have been studied as new ligands for the enantioselective transfer hydrogenation of prochiral ketones. High yields and excellent enantioselectivity up to >99 % ee have been achieved with an in situ generated catalytic system containing dichlorotris(triphenylphosphine)ruthenium and 2,6‐bis‐([4R,5R]‐4,5‐diphenyl‐4,5‐dihydro‐1H‐imidazol‐2‐yl)‐pyridine ( 3a ) in the presence of sodium isopropoxide.     

Novel Tacrine‐Grafted Ugi Adducts as Multipotent Anti‐Alzheimer Drugs: A Synthetic Renewal in Tacrine–Ferulic Acid Hybrids

Herein we describe the design, multicomponent synthesis, and biological, molecular modeling and ADMET studies, as well as in vitro PAMPA‐blood–brain barrier (BBB) analysis of new tacrine–ferulic acid hybrids (TFAHs). We identified (E)‐3‐(hydroxy‐3‐methoxyphenyl)‐N‐{8[(7‐methoxy‐1,2,3,4‐tetrahydroacridin‐9‐yl)amino]octyl}‐N‐[2‐(naphthalen‐2‐ylamino)2‐oxoethyl]acrylamide (TFAH 10 n ) as a particularly interesting multipotent compound that shows moderate and completely selective inhibition of human butyrylcholinesterase (IC₅₀=68.2 nM ), strong antioxidant activity (4.29 equiv trolox in an oxygen radical absorbance capacity (ORAC) assay), and good β‐amyloid (Aβ) anti‐aggregation properties (65.6 % at 1:1 ratio); moreover, it is able to permeate central nervous system (CNS) tissues, as determined by PAMPA‐BBB assay. Notably, even when tested at very high concentrations, TFAH 10 n easily surpasses the other TFAHs in hepatotoxicity profiling (59.4 % cell viability at 1000 μM ), affording good neuroprotection against toxic insults such as Aβ_1–40, Aβ_1–42, H₂O₂, and oligomycin A/rotenone on SH‐SY5Y cells, at 1 μM . The results reported herein support the development of new multipotent TFAH derivatives as potential drugs for the treatment of Alzheimer′s disease.     

Heme Oxygenase Inhibition by 1‐Aryl‐2‐(1H‐imidazol‐1‐yl/1H‐1,2,4‐triazol‐1‐yl)ethanones and Their Derivatives

Previous studies by our research group have been concerned with the design of selective inhibitors of heme oxygenases (HO‐1 and HO‐2). The majority of these were based on a four‐carbon linkage of an azole, usually an imidazole, and an aromatic moiety. In the present study, we designed and synthesized a series of inhibition candidates containing a shorter linkage between these groups, specifically, a series of 1‐aryl‐2‐(1H‐imidazol‐1‐yl/1H‐1,2,4‐triazol‐1‐yl)ethanones and their derivatives. As regards HO‐1 inhibition, the aromatic moieties yielding best results were found to be halogen‐substituted residues such as 3‐bromophenyl, 4‐bromophenyl, and 3,4‐dichlorophenyl, or hydrocarbon residues such as 2‐naphthyl, 4‐biphenyl, 4‐benzylphenyl, and 4‐(2‐phenethyl)phenyl. Among the imidazole‐ketones, five ( 36 – 39 , and 44 ) were found to be very potent (IC₅₀<5 μM ) toward both isozymes. Relative to the imidazole‐ketones, the series of corresponding triazole‐ketones showed four compounds ( 54 , 55 , 61 , and 62 ) having a selectivity index >50 in favor of HO‐1. In the case of the azole‐dioxolanes, two of them ( 80 and 85 ), each possessing a 2‐naphthyl moiety, were found to be particularly potent and selective HO‐1 inhibitors. Three non‐carbonyl analogues ( 87 , 89 , and 91 ) of 1‐(4‐chlorophenyl)‐2‐(1H‐imidazol‐1‐yl)ethanone were found to be good inhibitors of HO‐1. For the first time in our studies, two azole‐based inhibitors ( 37 and 39 ) were found to exhibit a modest selectivity index in favor of HO‐2. The present study has revealed additional candidates based on inhibition of heme oxygenases for potentially useful pharmacological and therapeutic applications.     

Effects of the Tumor‐Vasculature‐Disrupting Agent Verubulin and Two Heteroaryl Analogues on Cancer Cells,Endothelial Cells,and Blood Vessels

Two analogues of the discontinued tumor vascular‐disrupting agent verubulin (Azixa®, MPC‐6827, 1 ) featuring benzo‐1,4‐dioxan‐6‐yl (compound 5 a ) and N‐methylindol‐5‐yl (compound 10 ) residues instead of the para‐anisyl group on the 4‐(methylamino)‐2‐methylquinazoline pharmacophore, were prepared and found to exceed the antitumor efficacy of the lead compound. They were antiproliferative with single‐digit nanomolar IC₅₀ values against a panel of nine tumor cell lines, while not affecting nonmalignant fibroblasts. Indole 10 surpassed verubulin in seven tumor cell lines including colon, breast, ovarian, and germ cell cancer cell lines. In line with docking studies indicating that compound 10 may bind the colchicine binding site of tubulin more tightly (E_bind=?9.8 kcal mol^?1) than verubulin (E_bind=?8.3 kcal mol^?1), 10 suppressed the formation of vessel‐like tubes in endothelial cells and destroyed the blood vessels in the chorioallantoic membrane of fertilized chicken eggs at nanomolar concentrations. When applied to nude mice bearing a highly vascularized 1411HP germ cell xenograft tumor, compound 10 displayed pronounced vascular‐disrupting effects that led to hemorrhages and extensive central necrosis in the tumor.     

Synthesis and Biological Evaluation of 1‐Methyl‐1H‐indole–Pyrazoline Hybrids as Potential Tubulin Polymerization Inhibitors

A series of 1‐methyl‐1H‐indole–pyrazoline hybrids were designed, synthesized, and biologically evaluated as potential tubulin polymerization inhibitors. Among them, compound e19 [5‐(5‐bromo‐1‐methyl‐1H‐indol‐3‐yl)‐3‐(3,4,5‐trimethoxyphenyl)‐4,5‐dihydro‐1H‐pyrazole‐1‐carboxamide] showed the most potent inhibitory effect on tubulin assembly (IC₅₀=2.12 μm ) and in vitro growth inhibitory activity against a panel of four human cancer cell lines (IC₅₀ values of 0.21–0.31 μm ). Further studies confirmed that compound e19 can induce HeLa cell apoptosis, cause cell‐cycle arrest in G₂/M phase, and disrupt the cellular microtubule network. These studies, along with molecular docking and 3D‐QSAR modeling, provide an important basis for further optimization of compound e19 as a potential anticancer agent.     

Design and Synthesis of DNA‐Interactive β‐Carboline–Oxindole Hybrids as Cytotoxic and Apoptosis‐Inducing Agents

A new series of (E)‐3‐[(1‐aryl‐9H‐pyrido[3,4‐b]indol‐3‐yl)methylene]indolin‐2‐one hybrids were synthesized and evaluated for their in vitro cytotoxic activity against a panel of selected human cancer cell lines, namely, HCT‐15, HCT‐116, A549, NCI‐H460, and MCF‐7, including HFL. Among the tested compounds, (E)‐1‐benzyl‐5‐bromo‐3‐{[1‐(2,5‐dimethoxyphenyl)‐9H‐pyrido[3,4‐b]indol‐3‐yl]methylene}indolin‐2‐one ( 10 s ) showed potent cytotoxicity against HCT‐15 cancer cells with an IC₅₀ value of 1.43±0.26 μm and a GI₅₀ value of 0.89±0.06 μm . Notably, induction of apoptosis by 10 s on the HCT‐15 cell line was characterized by using different staining techniques, such as acridine orange/ethidium bromide (AO/EB) and DAPI. Further, to understand the mechanism of anticancer effects, various assays such as annexin V‐FITC/PI, DCFDA, and JC‐1were performed. The flow cytometric analysis revealed that compound 10 s arrests the HCT‐15 cancer cells at the G0/G1 phase of the cell cycle. Additionally, western blot analysis indicated that treatment of 10 s on HCT‐15 cancer cells led to decreased expression of anti‐apoptotic Bcl‐2 and increased protein expression of both pro‐apoptotic Bax and caspase‐3, ‐8, and ‐9, and cleaved PARP with reference to actin. Next, a clonogenic assay revealed the inhibition of colony formation in HCT‐15 cancer cells by 10 s in a dose‐dependent manner. Moreover, upon testing on normal human lung cells (HFL), the compounds were observed to be safer with a low toxicity profile. In addition, viscosity and molecular‐docking studies showed that compound 10 s has typical intercalation with DNA.     

Gold(I)‐Catalyzed Tandem Alkoxylation/Lactonization of γ‐Hydroxy‐α,β‐Acetylenic Esters

The formation of 4‐alkoxy‐2(5H)‐furanones was achieved via tandem alkoxylation/lactonization of γ‐hydroxy‐α,β‐acetylenic esters catalyzed by 2 mol% of [2,6‐bis(diisopropylphenyl)imidazol‐2‐ylidine]gold bis(trifluoromethanesulfonyl)imidate [Au(IPr)(NTf₂)]. The economic and simple procedure was applied to a series of various secondary propargylic alcohols allowing for yields of desired product of up to 95%. In addition, tertiary propargylic alcohols bearing mostly cyclic substituents were converted into the corresponding spiro derivatives. Both primary and secondary alcohols reacted with propargylic alcohols at moderate temperatures (65–80 °C) in either neat reactions or using 1,2‐dichloroethane as a reaction medium allowing for yields of 23–95%. In contrast to [Au(IPr)(NTf₂)], reactions with cationic complexes such as [2,6‐bis(diisopropylphenyl)imidazol‐2‐ylidine](acetonitrile)gold tetrafluoroborate [Au(IPr)(CH₃CN)][BF₄] or (μ‐hydroxy)bis{[2,6‐bis(diisopropylphenyl)imidazol‐2‐ylidine]gold} tetrafluoroborate or bis(trifluoromethanesulfonyl)imidate – [{Au(IPr)}₂(μ‐OH)][X] (X=BF₄, NTf₂) – mostly stop after the alkoxylation. Analysis of the intermediate proved the exclusive formation of the E‐isomer which allows for the subsequent lactonization.     

Synthesis and Biological Evaluation of Imidazo[2,1‐b][1,3,4]thiadiazole‐Linked Oxindoles as Potent Tubulin Polymerization Inhibitors

A series of imidazo[2,1‐b][1,3,4]thiadiazole‐linked oxindoles composed of an A, B, C and D ring system were synthesized and investigated for anti‐proliferative activity in various human cancer cell lines; test compounds were variously substituted at rings C and D. Among them, compounds 7 ((E)‐5‐fluoro‐3‐((6‐p‐tolyl‐2‐(3,4,5‐trimethoxyphenyl)‐imidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one), 11 ((E)‐3‐((6‐p‐tolyl‐2‐(3,4,5‐trimethoxyphenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one), and 15 ((E)‐6‐chloro‐3‐((6‐phenyl‐2‐(3,4,5‐trimethoxyphenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one) exhibited potent anti‐proliferative activity. Treatment with these three compounds resulted in accumulation of cells in G₂/M phase, inhibition of tubulin assembly, and increased cyclin‐B1 protein levels. Compound 7 displayed potent cytotoxicity, with an IC₅₀ range of 1.1–1.6 μM , and inhibited tubulin polymerization with an IC₅₀ value (0.15 μM ) lower than that of combretastatin A‐4 (1.16 μM ). Docking studies reveal that compounds 7 and 11 bind with αAsn101, βThr179, and βCys241 in the colchicine binding site of tubulin.