Bioisosteric Replacement Research Articles

Design, synthesis and stepwise optimization of nitrile-based inhibitors of cathepsins B and L

Human cathepsin B (CatB) is an important biological target in cancer therapy. In this work, we performed a knowledge-based design approach and the synthesis of a new set of 19 peptide-like nitrile-based cathepsin inhibitors. Reported compounds were assayed against a panel of human cysteine proteases: CatB, CatL, CatK, and CatS. Three compounds (7h, 7i, and 7j) displayed nanomolar inhibition of CatB and selectivity over CatK and CatL. The selectivity was achieved by using the combination of a para biphenyl ring at P3, halogenated phenylalanine in P2 and Thr-O-Bz group at P1. Likewise, compounds 7i and 7j showed selective CatB inhibition among the panel of enzymes studied. We have also described a successful example of bioisosteric replacement of the amide bond for a sulfonamide one [7e → 6b], where we observed an increase in affinity and selectivity for CatB while lowering the compound lipophilicity (ilogP). Our knowledge-based design approach and the respective structure–activity relationships provide insights into the specific ligand-target interactions for therapeutically relevant cathepsins.

Synthesis of nature product kinsenoside analogues with anti-inflammatory activity

Kinsenoside is the major bioactive component from herbal medicine with a broad range of pharmacological functions. Goodyeroside A, an epimer of kinsenoside, remains less explored. In this report we chemically synthesized kinsenoside, goodyeroside A and their analogues with glycan variation, chirality inversion at chiral center(s), and bioisosteric replacement of lactone with lactam. Among these compounds, goodyeroside A and its mannosyl counterpart demonstrated superior anti-inflammatory efficacy. Furthermore, goodyeroside A was found to suppresses inflammatory through inhibiting NF-κB signal pathway, effectively. Structure-activity relationship is also explored for further development of more promising kinsenoside analogues as drug candidates.

Novel Benzoxazin-3-one Derivatives: Design, Synthesis, Molecular Modeling, Anti-HIV-1 and Integrase Inhibitory Assay.

Integrase is a validated drug target for anti-HIV-1 therapy. The second generation integrase inhibitors display π-stacking interaction ability with 3'-end nucleotide as a streamlined metal chelating pharmacophore. In this study, we introduced benzoxazin-3-one scaffold for integrase inhibitory potential as bioisostere replacement strategy of 2-benzoxazolinone. Molecular modeling studies revealed that amide functionality alongside oxadiazole heteroatoms and sulfur in the second position of oxadiazole ring could mimic the metal chelating pharmacophore. The halobenzyl ring occupies hydrophobic site created by the cytidylate nucleotide (DC-16). The most potent and selective compound displayed 110 μM IC50 with a selectivity index of more than 2.

Synthesis of some new benzoxazole derivatives and investigation of their anticancer activities.

Phortress is an anticancer prodrug, which has active metabolite (5F-203) being potent agonist of the aryl hydrocarbon receptor (AhR). The 5F-203 switches on cytochrome P450 CYP1A1 gene expression and thus exhibits anticancer activity. In this study, it is aimed to obtain new phortress analogues by bioisosteric replacement of benzothiazole core in the structure to benzoxazole ring system. Synthesis of compounds (3a-3p) were performed according to literature methods. Their structures were elucidated by IR, 1H NMR, 13C NMR, 2D-NMR and HRMS spectroscopic methods. Cytotoxicity (MTT), inhibition of DNA synthesis and flow cytometric analysis assays were applied to determine anticancer activity of the compounds on colon (HT-29), breast (MCF7), lung (A549), liver (HepG2) and brain (C6) carcinoma cell types. When compared reference agent doxorubicin, compounds 3m and 3n displayed very attractive anticancer effect against carcinogenic cell lines. Due to structural similarity to phortress, biotransformation studies for 3m and 3n were examined by LCMS-IT-TOF system and probable metabolites of these compounds were determined. Induction potential of these compounds on CYP1A1/2 enzymes was also investigated to clarify possible mechanism of action. Interaction modes between CYP1A1 enzyme and compound 3n or its some metabolites were investigated by docking studies. In conclusion, findings of these study indicate that compounds 3m and 3n possess significant anticancer activity, probably with the same mechanism of action to Phortress.

Novel tetrazole-based selective COX-2 inhibitors: Design, synthesis, anti-inflammatory activity, evaluation of PGE2, TNF-α, IL-6 and histopathological study

To search for effective and selective COX-2 inhibitors, four novel series of tetrazole derivatives were designed based on bioisosteric replacement of SO2NH2 in celecoxib with tetrazole ring incorporating different central moieties as chalcone (2a-f), isoxazole (3a-c) or pyrazole (4a-c &5a-c). Target tetrazoles were synthesized and their structures were confirmed by spectroscopic techniques and elemental analyses. All target compounds were more selective for COX-2 isozyme than COX-1 when compared to standard drugs indomethacin and celecoxib. Compounds 3b, 3c, 4b, 4c, 5b and 5c exhibited potent in vitro COX-2 inhibitory activity (IC50 = 0.039–0.065 μM). Trimethoxy derivatives 3c, 4c and 5c acquired superior COX-2 selectivity index values (SI = 297.67–317.95) and were 1.1 fold higher than celecoxib (SI = 282.22). The most active six compounds were evaluated for their in vivo anti-inflammatory activity and serum levels of PGE2, TNF-α and IL-6 in addition to their ulcerogenic liability and histopathological profile. At a dose of 50 mg/Kg, compounds 3c and 5c showed better anti-inflammatory activity (% edema inhibition = 29.209–42.643) than celecoxib (% edema inhibition = 28.694–40.114) at different time intervals and were less ulcerogenic (UI = 0.123 and 0.11 in sequent) than celecoxib (UI = 0.167). Also, they displayed potent inhibitory effect on the production of PGE2 (% inhibition = 81.042 and 82.724 in sequent) greater than celecoxib (% inhibition = 79.666). Compound 5c decreased rat serum concentrations of both TNF-α (% inhibition = 55.349) and IL-6 (% inhibition = 61.561) in a comparable or better activity to celecoxib as reference drug. Finally, docking poses of the most active compounds showed strong binding interactions and effective overall docking energy scores explaining their remarkable COX-2 inhibitory activity.

Organotin (IV) complexes from Schiff bases ligands based on 2-amino-3-hydroxypyridine: synthesis, characterization, and cytotoxicity

A multicomponent reaction was used as a synthetic strategy to prepare organotin (IV) complexes, 2-amino-3-hydroxypyridine, saliciladehydes 5-R-substituted (H, CH3, OCH3, C(CH)3, F, Cl, Br, I, NO2), and dibutyltin(IV) oxide were used as starting materials. The complexes were analyzed by IR, UV–Visible, MS, NMR of 1H, 13C, 119Sn. The complex 3a was structurally identified by X-ray crystallography, which revealed a dimeric arrangement where the tin atom possess a distorted hexacoordinated environment in which the deprotonated phenolic oxygen atoms and the nitrogen atom of the azomethine from the ligand are coordinated to the metallic center, and one of the phenoxy oxygens bridges with the tin through an intermolecular interaction forming a planar Sn2O2 core. As strategy of molecular design, isosteric and bioisosteric replacement of halogens were employed. All organotin compounds were assessed for their in vitro cytotoxic activity on cancer cell lines K‐562 (chronic myelogenous leukemia), U‐251 (glioblastoma), HCT‐15 (human colorectal cancer), MCF‐7, MDA-MB-231 (human breast cancer), and SKLU‐1 (non‐small‐cell lung cancer). They evidenced an elevated cytotoxic activity, and the inhibitory percentage values stated higher activity than the cis-platin. The K-562 and MDA-MB-231 cells were more sensitive to organotin (IV) complexes than HCT-15 and MCF-7. The organotin (IV) compounds were also tested in vivo for brine shrimp lethality to examine their toxic properties.

Squaramides as Bioisosteres in Contemporary Drug Design.

Squaramides represent a class of vinylogous amides that are derived from the squarate oxocarbon dianion. While they have been known since the 1950s, squaramides have only recently emerged (in the last 10-20 years) as particularly useful chemical entities in a variety of applications. They have found particular use as bioisosteric replacements of several heteroatomic functional groups, notably ureas, thioureas, guanidines, and cyanoguanidines, owing in part to their similar capacity toward hydrogen bonding and ability to reliably engender defined conformations in drug ligands. This Review aims to provide a comprehensive overview of the deployment of squaramides as bioisosteres within the drug design landscape. Their utility in this space is further rationalized through an examination of the physicochemical properties of squaramides in contrast to other functional groups. In addition, we consider the deployment of related cyclic oxocarbanion derivatives as potential bioisosteric replacements of ureas and related functional groups.

MolOpt: A Web Server for Drug Design using Bioisosteric Transformation.

Bioisosteric replacement is widely used in drug design for lead optimization. However, the identification of a suitable bioisosteric group is not an easy task. In this work, we present MolOpt, a web server for in silico drug design using bioisosteric transformation. Potential bioisosteric transformation rules were derived from data mining, deep generative machine learning and similarity comparison. MolOpt tries to assist the medicinal chemist in his/her search for what to make next. By replacing molecular substructures with similar chemical groups, MolOpt automatically generates lists of analogues. MolOpt also evaluates forty important pharmacokinetic and toxic properties for each newly designed molecule. The transformed analogues can be assessed for possible future study. MolOpt is useful for the identification of suitable lead optimization ideas. The MolOpt Server is freely available for use on the web at http://xundrug.cn/molopt.

Turning Donepezil into a Multi-Target-Directed Ligand through a Merging Strategy.

Thanks to the widespread use and safety profile of donepezil (1) in the treatment of Alzheimer's disease (AD), one of the most widely adopted multi-target-directed ligand (MTDL) design strategies is to modify its molecular structure by linking a second fragment carrying an additional AD-relevant biological property. Herein, supported by a proposed combination therapy of 1 and the quinone drug idebenone, we rationally designed novel 1-based MTDLs targeting Aβ and oxidative pathways. By exploiting a bioisosteric replacement of the indanone core of 1 with a 1,4-naphthoquinone, we ended up with a series of highly merged derivatives, in principle devoid of the "physicochemical challenge" typical of large hybrid-based MTDLs. A preliminary investigation of their multi-target profile identified 9, which showed a potent and selective butyrylcholinesterase inhibitory activity, together with antioxidant and antiaggregating properties. In addition, it displayed a promising drug-like profile.

Structure-activity relationships for a series of (Bis(4-fluorophenyl)methyl)sulfinylethyl-aminopiperidines and -piperidine amines at the dopamine transporter: Bioisosteric replacement of the piperazine improves metabolic stability.

Despite considerable efforts to develop medications to treat psychostimulant use disorders, none have proven effective, leaving an underserved patient population and unanswered questions as to what mechanism(s) of action should be targeted for developing pharmacotherapies. Atypical dopamine transporter (DAT) inhibitors, based on (±)modafinil, have shown therapeutic potential in preclinical models of psychostimulant abuse. However, metabolic instability among other limitations to piperazine analogues 1-3 have impeded further development. Herein, bioisosteric substitutions of the piperazine ring were explored with a series of aminopiperidines (A) and piperidine amines (B) wherein compounds with either a terminal tertiary amine or amide were synthesized. Several lead compounds showed high to moderate DAT affinities and metabolic stability in rat liver microsomes. Aminopiperidines 7 (DAT Ki=50.6nM), 21b (DAT Ki=77.2nM) and 33 (DAT Ki=30.0nM) produced only minimal stimulation of ambulatory activity in mice, compared to cocaine, suggesting an atypical DAT inhibitor profile.

Stepwise Design of γ-Secretase Modulators with an Advanced Profile by Judicious Coordinated Structural Replacements and an Unconventional Phenyl Ring Bioisostere.

Starting from RO6800020 (1), our former γ-secretase modulator (GSM) lead compound, we utilized sequential structural replacements to improve the potency (IC50), pharmacokinetic properties including the free fraction (fraction unbound (fu)) in plasma, and in vivo efficacy. Importantly, we used novel CF3-alkoxy groups as bioisosteric replacements of a fluorinated phenyl ring and properties such as lipophilicity, solubility, metabolic stability, and free fraction could be balanced, maintaining low Pgp efflux needed for CNS penetration. In addition, by reducing aromaticity, we prevented phototoxicity. Additional substitution in the triazolopyridine core disturbed the binding to phosphatidylinositol 4-kinase, catalytic β (PIK4CB). We also introduced less lipophilic head heterocycles devoid of covalent binding (CVB) liability. After these changes, further modifications to the trifluoroethoxy bioisosteric replacement allowed rebalancing of properties, such as lipophilicity, and also potency. Our optimization strategy culminated with in vivo active RO7101556 (18B) having excellent properties and being selected as an advanced candidate.

Fused and Substituted Pyrimidine Derivatives as Profound Anti-Cancer Agents.

The rationale behind drug design is the strategic utilization of heterocyclic fragments with specific physicochemical properties to form molecular targeted agents. Among the heterocyclic molecules, pyrimidine has proved to be a privileged pharmacophore for various biological cancer targets. The anti-cancer potential of small molecules with fused and substituted pyrimidines can be enhanced through bioisosteric replacements and altering their ADME parameters. Although several small molecules are used in cancer chemotherapy, oncology therapeutics has various limitations, especially in their routes of administration and their concurrent side effects. Such pernicious effects may be overcome, via selective biological targeting. In this review, the biological targets, to inhibit cancer, have been discussed. The structural activity relationship of fused and substituted pyrimidines was studied. Eco-friendly synthetic approaches for pyrimidine derivatives have also been discussed. This review will give an insight to scientists and researchers of medicinal chemistry discipline to design small molecules having a pyrimidine scaffold with high anti-cancer potential.

Synthesis and antimycobacterial evaluation of pyridinyl- and pyrazinylhydrazone derivatives

Bioisosteric replacements are often tried goaling to affect the lipophilicity, polarity, and aqueous solubility of the substances, as a way to obtain therapeutically improved medicines. Also, hydrazonyl compounds are described with a wide range of pharmacological activities, having also recognized activities in antimycobacterial field. In this study, twenty-seven pyrimidinyl and pyrazinyl derivatives have been synthesized and evaluated for their antimycobacterial activity against M. tuberculosis ATTC 27294. The componds were obtained by the reaction of 2-hydrazinylpyridine, 4-hydrazinylpyridine, or 2-hydrazinylpyrazine with appropriated aromatic or heteroaromatic aldehydes. Antimycobacterial activity of the compounds was determined according to MTT assay. The most active compound, a 2-hydroxyl-5-nitrophenyl-4-pyridinylhydrazone derivative, showed good biodisponibility and nonmutagenic or tumorigenic profiles in preliminaries in silico studies, and exceptional in vitro activity, being compared with the reference drug ethambutol. This study supports that pyrimidinyl and pyrazinyl derivatives may be used for the development of new tuberculostatic agents.

Nitrogen-Walk Approach to Explore Bioisosteric Replacements in a Series of Potent A2B Adenosine Receptor Antagonists.

A systematic exploration of bioisosteric replacements for furan and thiophene cores in a series of potent A2BAR antagonists has been carried out using the nitrogen-walk approach. A collection of 42 novel alkyl 4-substituted-2-methyl-1,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylates, which contain 18 different pentagonal heterocyclic frameworks at position 4, was synthesized and evaluated. This study enabled the identification of new ligands that combine remarkable affinity (Ki < 30 nM) and exquisite selectivity. The structure-activity relationship (SAR) trends identified were substantiated by a molecular modeling study, based on a receptor-driven docking model and including a systematic free energy perturbation (FEP) study. Preliminary evaluation of the CYP3A4 and CYP2D6 inhibitory activity in optimized ligands evidenced weak and negligible activity, respectively. The stereospecific interaction between hA2BAR and the eutomer of the most attractive novel antagonist (S)-18g (Ki = 3.66 nM) was validated.

2-Arylbenzo[d]oxazole Phosphinate Esters as Second-Generation Modulators of Utrophin for the Treatment of Duchenne Muscular Dystrophy.

Utrophin modulation is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD), which should be applicable to all patient populations. Following on from ezutromid, the first-generation utrophin modulator, we describe the development of a second generation of utrophin modulators, based on the bioisosteric replacement of the sulfone group with a phosphinate ester and substitution of the metabolically labile naphthalene with a haloaryl substituent. The improved physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties, further reflected in the enhanced pharmacokinetic profile of the most advanced compounds, 30 and 27, led to significantly better in vivo exposure compared to ezutromid and alleviation of the dystrophic phenotype in mdx mice. While 30 was found to have dose-limiting hepatotoxicity, 27 and its enantiomers exhibited limited off-target effects, resulting in a safe profile and highlighting their potential utility as next-generation utrophin modulators suitable for progression toward a future DMD therapy.

Side chain virtual screening of matched molecular pairs: a PDB-wide and ChEMBL-wide analysis.

Optimization in medicinal chemistry often involves designing replacements for a section of a molecule which aim to retain potency while improving other properties of the compound. In this study, we perform a retrospective analysis using a number of computational methods to identify active side chains amongst a pool of random decoy side chains, mimicking a similar procedure that might be undertaken in a real medicinal chemistry project. We constructed a dataset derived from public ChEMBL and PDB data by identifying all ChEMBL assays where at least one of the compounds tested has also been co-crystallized in the PDB. Additionally, we required that there be at least ten active compounds tested in the same ChEMBL assay that are matched molecular pairs to the crystallized ligand. Using the compiled dataset consisting of sets of compounds from 402 assays, we have tested a number of methods for scoring side chains including Spark, a bioisostere replacement tool from Cresset, molecular docking using Glide from Schrodinger, docking with Smina, as well as other methods. In this work, we present a comparison of the performance of these methods in discriminating active side chains from decoys as well as recommendations for circumstances when different methods should be used.

Synthesis, antiinflammatory activity, and molecular docking studies of bisphosphonic esters as potential MMP-8 and MMP-9 inhibitors.

Bisphosphonic acids (or bisphosphonates) have been successfully used in the clinic treatment of bone diseases for over decades. Additionally, the antiinflammatory activity of these compounds has been gaining attention. In our previous work, we synthesized and in vivo evaluated the bisphosphonic esters 1 and 2, finding a moderate edema inhibition upon oral and topical administration on BALB/c mice. Thus, in this work, the bioisosteric replacement of an amide functional group for an ester afforded the new bisphosphonates 3–6, which had a moderate oral edema inhibition (25 mg/kg dose) and a significant topical antiinflammatory activity (2 mg/ear) on BALB/c mice, with 6 being the most active hit (55.9% edema inhibition), comparable to the positive control (55.5% edema inhibition) on a TPA topical model. Next, to assess the acute toxicity of the synthesized derivatives, test animals were administered with 50–100 mg/kg of 3–6, respectively, by an oral route, and after 14 days, neither lethality nor a significative weight loss were observed. Finally, a structure–activity relationship (SAR) and a molecular docking analysis of 3–6 helped us to explain the trend observed in biological tests. Considering all these aspects, we propose the inhibition of MMP-8 and MMP-9 as a possible action mechanism of the synthesized derivatives.

Mitigation of heterocyclic aromatic amines in cooked meat. Part I: Informed selection of antioxidants based on molecular modeling

This work aimed to develop a method permitting an informed choice of antioxidants to reduce carcinogenic heterocyclic aromatic amine (HAA) formation during proteinaceous food cooking. Therefore, a three-step approach was developed. First, the most promising antioxidants were selected using molecular modeling approaches. For this, analog design was used to highlight the most suitable antioxidants based on their diversification potential using bioisosteric replacement. Then, structure activity relationship studies allowed drawing the relevant properties for inhibiting HAA formation and explained partly the inhibitory activity. Secondly, the approved antioxidants were tested in ground beef patties to assess their inhibitory properties against HAA formation. Resveratrol was found to be the most efficient as it totally inhibited MeIQ and reduced MeIQx and PhIP formation by 40 and 70%, respectively. Finally, natural ingredients rich in these antioxidants were evaluated. Oregano was found to totally inhibit MeIQ formation and to reduce by half MeIQx and PhIP formation.

Design synthesis and evaluation of novel aldose reductase inhibitors: The case of indolyl–sulfonyl–phenols

Therapeutic interventions with aldose reductase inhibitors appear to be a promising approach to major pathological conditions (i.e. neuropathy/angiopathy related to chronic hyperglycemia, chronic inflammation and cancer). Until now, the most potent aldose reductase inhibitors have been carboxylic acid derivatives, which poorly permeate biological membranes. In this work, continuing our previous works, we promote the bioisosteric replacement of the carboxylic acid moiety to make equally potent yet more druggable inhibitors.

Synthesis, Radiosynthesis and Biological Evaluation of Buprenorphine-Derived Phenylazocarboxamides as Novel μ-Opioid Receptor Ligands.

Targeted structural modifications have led to a novel type of buprenorphine‐derived opioid receptor ligand displaying an improved selectivity profile for the μ‐OR subtype. On this basis, it is shown that phenylazocarboxamides may serve as useful bioisosteric replacements for the widely occurring cinnamide units, without loss of OR binding affinity or subtype selectivity. This study further includes functional experiments pointing to weak partial agonist properties of the novel μ‐OR ligands, as well as docking and metabolism experiments. Finally, the unique bifunctional character of phenylazocarboxylates, herein serving as precursors for the azocarboxamide subunit, was exploited to demonstrate the accessibility of an 18F‐fluorinated analogue.