Monoamine Oxidase (MAO) Inhibitory Activity: 3‐Phenylcoumarins versus 4‐Hydroxy‐3‐phenylcoumarins

Monoamine oxidase (MAO) is a useful target in the treatment of neurodegenerative diseases and depressive disorders. Both isoforms, MAO‐A and MAO‐B, are known to play critical roles in disease progression, and as such, the identification of novel, potent and selective inhibitors is an important research goal. Here, two series of 3‐phenylcoumarin derivatives were synthesized and evaluated against MAO‐A and MAO‐B. Most of the compounds tested acted preferentially on MAO‐B, with IC₅₀ values in the micromolar to nanomolar range. Only 6‐chloro‐4‐hydroxy‐3‐(2’‐hydroxyphenyl)coumarin exhibited activity against the MAO‐A isoform, while still retaining good selectivity for MAO‐B. 6‐Chloro‐3‐phenylcoumarins unsubstituted at the 4 position were found to be more active as MAO‐B inhibitors than the corresponding 4‐hydroxylated coumarins. For 4‐unsubstituted coumarins, meta and para positions on the 3‐phenyl ring seem to be the most favorable for substitution. Molecular docking simulations were used to explain the observed hMAO‐B structure–activity relationships for this type of compound. 6‐Chloro‐3‐(3’‐methoxyphenyl)coumarin was the most active compound identified (IC₅₀=0.001 μM ) and is several times more potent and selective than the reference compound, R‐(?)‐deprenyl hydrochloride. This compound represents a novel tool for the further investigation of the therapeutic potential of MAO‐B inhibitors.     

Design,Synthesis, and Evaluation of 2‐Amino‐6‐nitrobenzothiazole‐Derived Hydrazones as MAO Inhibitors: Role of the Methylene Spacer Group

A series of 2‐amino‐6‐nitrobenzothiazole‐derived extended hydrazones were designed, synthesized, and investigated for their ability to inhibit monoamine oxidase A and B (MAO‐A/MAO‐B). The compounds were found to exhibit inhibitory activities in the nanomolar to micromolar range. Some of the compounds showed excellent potency and selectivity against the MAO‐B isoform. N′‐(5‐Chloro‐2‐oxoindolin‐3‐ylidene)‐2‐(6‐nitrobenzothiazol‐2‐ylamino)acetohydrazide (compound 31 ) showed the highest MAO‐B inhibitory activity (IC₅₀=1.8±0.3 nm , selectivity index [SI]=766.67), whereas compound 6 [N′‐(1‐(4‐bromophenyl)ethylidene)‐2‐(6‐nitrobenzothiazol‐2‐ylamino)acetohydrazide] was found to be the most active MAO‐A inhibitor (IC₅₀=0.42±0.003 μm ). Kinetic studies revealed that compounds 6 and 31 exhibit competitive‐type reversible inhibition against both MAO‐A and MAO‐B, respectively. Structure–activity relationship (SAR) studies disclosed several structural aspects significant for potency and the contribution of the methylene spacer toward MAO‐B inhibitory potency, with minimal or no neurotoxicity. Molecular modeling studies yielded a good correlation between experimental and theoretical inhibitory data. Binding pose analysis revealed the significance of cumulative effects of π–π stacking and hydrogen bond interactions for effective stabilization of virtual ligand–protein complexes. Further optimization studies of compound 31 , including co‐crystallization of inhibitor–MAO‐B complexes, are essential to develop these compounds as potential therapeutic agents for MAO‐B‐associated neurodegenerative diseases.     

Synthesis,Biological Evaluation and Molecular Modeling Studies of Propargyl‐Containing 2,4,6‐Trisubstituted Pyrimidine Derivatives as Potential Anti‐Parkinson Agents

Monoamine oxidase B (MAO‐B) inhibitors are potential drug candidates for the treatment of various neurological disorders including Parkinson's disease. A total of 20 new propargyl‐containing 2,4,6‐trisubstituted pyrimidine derivatives were synthesized and screened for MAO inhibition using Amplex Red assays. All the synthesized compounds were found to be reversible and selective inhibitors of the MAO‐B isoform at sub‐micromolar concentrations. MVB3 was the most potent MAO‐B inhibitor with an IC₅₀ value of 0.38±0.02 μμ , whereas MVB6 (IC₅₀=0.51±0.04 μμ ) and MVB16 (IC₅₀=0.48±0.06 μμ ) were the most selective for MAO‐B with a selectivity index of more than 100‐fold. In cytotoxic studies, these compounds were found to be nontoxic to human neuroblastoma SH‐SY5Y cells at concentrations of 25 μm . MVB6 was found to decrease the intracellular level of reactive oxygen species to 68 % at 10 μm concentration, whereas other compounds did not produce significant changes in reactive oxygen species levels. In molecular modeling studies, MVB3 displayed strong binding affinity for the MAO‐B isoform with a dock score of ?10.45, in agreement with the observed activity. All the compounds fitted well in the hydrophobic cavity of MAO‐B. Thus, propargyl‐substituted pyrimidine derivatives can be promising leads in the development of potent, selective and reversible MAO‐B inhibitors for the treatment of Parkinson's disease.     

MAO Inhibitory Activity of 2‐Arylbenzofurans versus 3‐Arylcoumarins: Synthesis,in vitro Study,and Docking Calculations

Monoamine oxidase (MAO) is an important drug target for the treatment of neurological disorders. Several 3‐arylcoumarin derivatives were previously described as interesting selective MAO‐B inhibitors. Preserving the trans‐stilbene structure, a series of 2‐arylbenzofuran and corresponding 3‐arylcoumarin derivatives were synthesized and evaluated as inhibitors of both MAO isoforms, MAO‐A and MAO‐B. In general, both types of derivatives were found to be selective MAO‐B inhibitors, with IC₅₀ values in the nano‐ to micromolar range. 5‐Nitro‐2‐(4‐methoxyphenyl)benzofuran ( 8 ) is the most active compound of the benzofuran series, presenting MAO‐B selectivity and reversible inhibition (IC₅₀=140 nM ). 3‐(4′‐Methoxyphenyl)‐6‐nitrocoumarin ( 15 ), with the same substitution pattern as that of compound 8 , was found to be the most active MAO‐B inhibitor of the coumarin series (IC₅₀=3 nM ). However, 3‐phenylcoumarin 14 showed activity in the same range (IC₅₀=6 nM ), is reversible, and also severalfold more selective than compound 15 . Docking experiments for the most active compounds into the MAO‐B and MAO‐A binding pockets highlighted different interactions between the derivative classes (2‐arylbenzofurans and 3‐arylcoumarins), and provided new information about the enzyme–inhibitor interaction and the potential therapeutic application of these scaffolds.     

Design,Synthesis, in vitro MAO‐B Inhibitory Evaluation,and Computational Studies of Some 6‐Nitrobenzothiazole‐Derived Semicarbazones

Monoamine oxidase B (MAO‐B) is an important drug target for the treatment of neurological disorders. A series of 6‐nitrobenzothiazole‐derived semicarbazones were designed, synthesized, and evaluated as inhibitors of the rat brain MAO‐B isoenzyme. Most of the compounds were found to be potent inhibitors of MAO‐B, with IC₅₀ values in the nanomolar to micromolar range. Molecular docking studies were performed with AutoDock 4.2 to deduce the affinity and binding mode of these inhibitors toward the MAO‐B active site. The free energies of binding (ΔG) and inhibition constants (K_i) of the docked compounds were calculated by the Lamarckian genetic algorithm (LGA) of AutoDock 4.2. Good correlations between the calculated and experimental results were obtained. 1‐[(4‐Chlorophenyl)(phenyl)methylene]‐4‐(6‐nitrobenzothiazol‐2‐yl)semicarbazide emerged as the lead MAO‐B inhibitor, with top ranking in both the experimental MAO‐B assay (IC₅₀: 0.004±0.001 μM ) and in computational docking studies (K_i: 1.08 μM ). Binding mode analysis of potent inhibitors suggests that these compounds are well accommodated by the MAO‐B active site through stable hydrophobic and hydrogen bonding interactions. Interestingly, the 6‐nitrobenzothiazole moiety is stabilized in the substrate cavity with the aryl or diaryl residues extending up into the entrance cavity of the active site. According to our results, docking experiments could be an interesting approach for predicting the activity and binding interactions of this class of semicarbazones against MAO‐B. Thus, a binding site model consisting of three essential pharmacophoric features is proposed, and this can be used for the design of future MAO‐B inhibitors.     

Exploration of a Library of 3,4‐(Methylenedioxy)aniline‐Derived Semicarbazones as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase: Design,Synthesis, and Evaluation

A library of 3,4‐(methylenedioxy)aniline‐derived semicarbazones was designed, synthesized, and evaluated as monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitors for the treatment of neurodegenerative diseases. Most of the new compounds selectively inhibited MAO‐B and AChE, with IC₅₀ values in the micro‐ or nanomolar ranges. Compound 16 , 1‐(2,6‐dichlorobenzylidene)‐4‐(benzo[1,3]dioxol‐5‐yl)semicarbazide presented a balanced multifunctional profile of MAO‐A (IC₅₀=4.52±0.032 μm ), MAO‐B (IC₅₀=0.059±0.002 μm ), and AChE (IC₅₀=0.0087±0.0002 μm ) inhibition without neurotoxicity. Kinetic studies revealed that compound 16 exhibits competitive and reversible inhibition against MAO‐A and MAO‐B, and mixed‐type inhibition against AChE. Molecular docking studies further revealed insight into the possible interactions within the enzyme–inhibitor complexes. The most active compounds were found to interact with the enzymes through hydrogen bonding and hydrophobic interactions. Additionally, in silico molecular properties and ADME properties of the synthesized compounds were calculated to explore their drug‐like characteristics.     

Synthesis,Biochemistry, and Computational Studies of Brominated Thienyl Chalcones: A New Class of Reversible MAO‐B Inhibitors

A series of (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐(para‐substituted phenyl)prop‐2‐en‐1‐ones ( TB1 – TB11 ) was synthesized and tested for inhibitory activity toward human monoamine oxidase (hMAO). All compounds were found to be competitive, selective, and reversible toward hMAO‐B except (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐(4‐nitrophenyl)prop‐2‐en‐1‐one ( TB7 ) and (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐(4‐chlorophenyl)prop‐2‐en‐1‐one ( TB8 ), which were selective inhibitors of hMAO‐A. The most potent compound, (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐[4‐(dimethylamino)phenyl]prop‐2‐en‐1‐one ( TB5 ), showed the best inhibitory activity and higher selectivity toward hMAO‐B, with K_i and SI values of 0.11±0.01 μm and 13.18, respectively. PAMPA assays for all compounds were carried out in order to evaluate the capacity of the compounds to cross the blood–brain barrier. Moreover, the most potent MAO‐B inhibitor, TB5 , was found to be nontoxic at 5 and 25 μm , with 95.75 and 84.59 % viability among cells, respectively. Molecular docking simulations were carried out to understand the crucial interactions responsible for selectivity and potency.     

3‐Amidocoumarins as Potential Multifunctional Agents against Neurodegenerative Diseases

Monoamine oxidase (MAO) generates reactive oxygen species (ROS), which cause neuronal cell death, causing neurodegeneration. Agents that are able to concurrently inhibit MAO and scavenge free radicals represent promising multifunctional neuroprotective agents that could be used to delay or slow the progression of neurodegenerative diseases. In this work, variously substituted 3‐amidocoumarins are described that exert neuroprotection in vitro against hydrogen peroxide in rat cortical neurons, as well as antioxidant activity in a 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH?) radical scavenging assay. Selective and reversible inhibitors of the MAO‐B isoform were identified. Interestingly, in the case of the 3‐benzamidocoumarins, substitution at position 4 with a hydroxy group abolishes MAO‐B activity, but the compounds remain active in the neuroprotection model. Further evaluation of 3‐heteroarylamide derivatives indicates that it is the nature of the heterocycle that determines the neuroprotective effects. Evaluation in a parallel artificial membrane permeability assay (PAMPA) highlighted the need to further improve the blood–brain barrier permeability of this compound class. However, the compounds described herein adhere to Lipinski′s rule of five, suggesting that this novel scaffold has desirable properties for the development of potential drug candidates.     

N‐Benzyl Substitution of Polyhydroxypyrrolidines: The Way to Selective Inhibitors of Golgi α‐Mannosidase II

Inhibition of the biosynthesis of complex N‐glycans in the Golgi apparatus influences progress of tumor growth and metastasis. Golgi α‐mannosidase II (GMII) has become a therapeutic target for drugs with anticancer activities. One critical task for successful application of GMII drugs in medical treatments is to decrease their unwanted co‐inhibition of lysosomal α‐mannosidase (LMan), a weakness of all known potent GMII inhibitors. A series of novel N‐substituted polyhydroxypyrrolidines was synthesized and tested with modeled GH38 α‐mannosidases from Drosophila melanogaster (GMIIb and LManII). The most potent structures inhibited GMIIb (K_i=50–76 μm , as determined by enzyme assays) with a significant selectivity index of IC₅₀(LManII)/IC₅₀(GMIIb) >100. These compounds also showed inhibitory activities in in vitro assays with cancer cell lines (leukemia, IC₅₀=92–200 μm ) and low cytotoxic activities in normal fibroblast cell lines (IC₅₀>200 μm ). In addition, they did not show any significant inhibitory activity toward GH47 Aspergillus saitoiα1,2‐mannosidase. An appropriate stereo configuration of hydroxymethyl and benzyl functional groups on the pyrrolidine ring of the inhibitor may lead to an inhibitor with the required selectivity for the active site of a target α‐mannosidase.     

Structure–Activity Relationship Studies on (R)‐PFI‐2 Analogues as Inhibitors of Histone Lysine Methyltransferase SETD7

SETD7 is a histone H3K4 lysine methyltransferase involved in human gene regulation. Aberrant expression of SETD7 has been associated with various diseases, including cancer. Therefore, SETD7 is considered a good target for the development of new epigenetic drugs. To date, few selective small‐molecule inhibitors have been reported that target SETD7, the most potent being (R)‐PFI‐2. Herein we report structure–activity relationship studies on (R)‐PFI‐2 and its analogues. A library of 29 structural analogues of (R)‐PFI‐2 was synthesized and evaluated for inhibition of recombinantly expressed human SETD7. The key interactions were found to be a salt bridge and a hydrogen bond formed between (R)‐PFI‐2′s NH₂⁺ group and SETD7′s Asp256 and His252 residue, respectively.     

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.     

5‐Benzylidenethiazolidin‐4‐ones as Multitarget Inhibitors of Bacterial Mur Ligases

Mur ligases participate in the intracellular path of bacterial peptidoglycan biosynthesis and constitute attractive, although so far underexploited, targets for antibacterial drug discovery. A series of hydroxy‐substituted 5‐benzylidenethiazolidin‐4‐ones were synthesized and tested as inhibitors of Mur ligases. The most potent compound 5 a was active against MurD–F with IC₅₀ values between 2 and 6 μm, making it a promising multitarget inhibitor of Mur ligases. Antibacterial activity against different strains, inhibitory activity against protein kinases, mutagenicity and genotoxicity of 5 a were also investigated, and kinetic and NMR studies were conducted.     

Design,Synthesis, and Biological Evaluation of Tetrahydro‐β‐carboline Derivatives as Selective Sub‐Nanomolar Gelatinase Inhibitors

Targeting matrix metalloproteinases (MMPs) is a pursued strategy for treating several pathological conditions, such as multiple sclerosis and cancer. Herein, a series of novel tetrahydro‐β‐carboline derivatives with outstanding inhibitory activity toward MMPs are present. In particular, compounds 9 f , 9 g , 9 h and 9 i show sub‐nanomolar IC₅₀ values. Interestingly, compounds 9 g and 9 i also provide remarkable selectivity toward gelatinases; IC₅₀=0.15 nm for both toward MMP‐2 and IC₅₀=0.63 and 0.58 nm , respectively, toward MMP‐9. Molecular docking simulations, performed by employing quantum mechanics based partial charges, shed light on the rationale behind binding involving specific interactions with key residues of S1′ and S3′ domains. Taken together, these studies indicate that tetrahydro‐β‐carboline represents a promising scaffold for the design of novel inhibitors able to target MMPs and selectively bias gelatinases, over the desirable range of the pharmacokinetics spectrum.     

Adamantyl Arotinoids That Inhibit IκB Kinase α and IκB Kinase β

A series of analogues of the adamantyl arotinoid (AdAr) chalcone MX781 with halogenated benzyloxy substituents at C2′ and heterocyclic derivatives replacing the chalcone group were found to inhibit IκBα kinase α (IKKα) and IκBα kinase β (IKKβ) activities. The growth inhibitory capacity of some analogues against Jurkat T cells as well as prostate carcinoma (PC‐3) and chronic myelogenous leukemia (K562) cells, which contain elevated basal IKK activity, correlates with the induction of apoptosis and increased inhibition of recombinant IKKα and IKKβ in vitro, pointing toward inhibition of IKK/NFκB signaling as the most likely target of the anticancer activities of these AdArs. While the chalcone functional group present in many dietary compounds has been shown to mediate interactions with IKKβ via Michael addition with cysteine residues, AdArs containing a five‐membered heterocyclic ring (isoxazoles and pyrazoles) in place of the chalcone of the parent system are potent inhibitors of IKKs as well, which suggests that other mechanisms for inhibition exist that do not depend on the presence of a reactive α,β‐unsaturated ketone.     

Synthesis and Structure–Activity Relationship Studies of 2‐(1,3,4‐Oxadiazole‐2(3H)‐thione)‐3‐amino‐5‐arylthieno[2,3‐b]pyridines as Inhibitors of DRAK2

In recent years, DAPK‐related apoptosis‐inducing protein kinase 2 (DRAK2) has emerged as a promising target for the treatment of a variety of autoimmune diseases and for the prevention of graft rejection after organ transplantation. However, medicinal chemistry optimization campaigns for the discovery of novel small‐molecule inhibitors of DRAK2 have not yet been published. Screening of a proprietary compound library led to the discovery of a benzothiophene analogue that displays an affinity constant (K_d) value of 0.25 μM . Variation of the core scaffold and of the substitution pattern afforded a series of 5‐arylthieno[2,3‐b]pyridines with strong binding affinity (K_d=0.008 μM for the most potent representative). These compounds also show promising activity in a functional biochemical DRAK2 enzyme assay, with an IC₅₀ value of 0.029 μM for the most potent congener. Selectivity profiling of the most potent compounds revealed that they lack selectivity within the DAPK family of kinases. However, one of the less potent analogues is a selective ligand for DRAK2 and can be used as starting point for the synthesis of selective and potent DRAK2 inhibitors.     

Synthesis and Evaluation of Novel Acyclic Nucleoside Phosphonates as Inhibitors of Plasmodium falciparum and Human 6‐Oxopurine Phosphoribosyltransferases

Acyclic nucleoside phosphonates (ANPs) are a promising class of antimalarial therapeutic drug leads that exhibit a wide variety of K_i values for Plasmodium falciparum (Pf) and human hypoxanthine‐guanine‐(xanthine) phosphoribosyltransferases [HG(X)PRTs]. A novel series of ANPs, analogues of previously reported 2‐(phosphonoethoxy)ethyl (PEE) and (R,S)‐3‐hydroxy‐2‐(phosphonomethoxy)propyl (HPMP) derivatives, were designed and synthesized to evaluate their ability to act as inhibitors of these enzymes and to extend our ongoing antimalarial structure–activity relationship studies. In this series, (S)‐3‐hydroxy‐2‐(phosphonoethoxy)propyl (HPEP), (S)‐2‐(phosphonomethoxy)propanoic acid (CPME), or (S)‐2‐(phosphonoethoxy)propanoic acid (CPEE) are the acyclic moieties. Of this group, (S)‐3‐hydroxy‐2‐(phosphonoethoxy)propylguanine (HPEPG) exhibits the highest potency for PfHGXPRT, with a K_i value of 0.1 μM and a K_i value for human HGPRT of 0.6 μM . The crystal structures of HPEPG and HPEPHx (where Hx=hypoxanthine) in complex with human HGPRT were obtained, showing specific interactions with active site residues. Prodrugs for the HPEP and CPEE analogues were synthesized and tested for in vitro antimalarial activity. The lowest IC₅₀ value (22 μM ) in a chloroquine‐resistant strain was observed for the bis‐amidate prodrug of HPEPG.     

Monoamine Oxidase Inhibitory Activity: Methyl‐ versus Chlorochalcone Derivatives

Numerous studies have shown that chalcones are promising scaffolds for the development of new monoamine oxidase‐B (MAO‐B) inhibitors. As a continuation of our ongoing research into the development of reversible human MAO‐B (hMAO‐B) inhibitors, two series of twenty chalcones containing electron‐donating and electron‐withdrawing substituents were synthesized. All compounds were found to be competitive, selective, and reversible inhibitors of hMAO‐B except (2E)‐1‐(4‐methylphenyl)‐3‐(4‐nitrophenyl)prop‐2‐en‐1‐one ( P7 ) and (2E)‐1‐(4‐chlorophenyl)‐3‐(4‐nitrophenyl)prop‐2‐en‐1‐one ( P17 ), which were found to be selective inhibitors of hMAO‐A. The most potent hMAO‐B inhibitor, (2E)‐1‐(4‐chlorophenyl)‐3‐(4‐ethylphenyl)prop‐2‐en‐1‐one ( P16 ), showed a K_i value of 0.11±0.01 μm . Molecular docking simulations were carried out to identify the hypothetical binding mode for the most potent compounds in the active sites of hMAO‐A and B. The ability of the compounds to cross the blood–brain barrier was assessed by parallel artificial membrane permeability assay (PAMPA). Additionally, the most potent hMAO‐B inhibitor P16 showed no toxicity in cultured hepatic cells at concentrations of 5 and 25 μm .     

2‐Carbaborane‐3‐phenyl‐1H‐indoles—Synthesis via McMurry Reaction and Cyclooxygenase (COX) Inhibition Activity

Cyclooxygenase‐2 (COX‐2) inhibitors have been the focus of medicinal chemistry efforts for years, and many compounds that exhibit high selectivity and affinity have been developed. As carbaboranes represent interesting pharmacophores as phenyl mimetics in drug development, this paper presents the synthesis of carbaboranyl derivatives of COX‐2‐selective 2,3‐disubstituted indoles. Despite the lability of carbaboranes under reducing conditions, 2‐carbaborane‐3‐phenyl‐1H‐indoles could be synthesized by McMurry cyclization of the corresponding amides. Whereas the meta‐carbaboranyl‐substituted derivatives lacked COX inhibitory activity, an ortho‐carbaboranyl analogue was active, but showed a selectivity shift toward COX‐1.