Medicinal Chemistry Strategies Research Articles

Discovery of quinazolin-4-one-based non-covalent inhibitors targeting the severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 Mpro)

The COVID-19 pandemic caused by SARS-CoV-2 continues to pose a great threat to public health while various vaccines are available worldwide. Main protease (Mpro) has been validated as an effective anti-COVID-19 drug target. Using medicinal chemistry and rational drug design strategies, we identified a quinazolin-4-one series of nonpeptidic, noncovalent SARS-CoV-2 Mpro inhibitors based on baicalein, 5,6,7-trihydroxy-2-phenyl-4H-chromen-4-one. In particular, compound C7 exhibits superior inhibitory activity against SARS-CoV-2 Mpro relative to baicalein (IC50 = 0.085 ± 0.006 and 0.966 ± 0.065 μM, respectively), as well as improved physicochemical and drug metabolism and pharmacokinetics (DMPK) properties. In addition, C7 inhibits viral replication in SARS-CoV-2-infected Vero E6 cells more effectively than baicalein (EC50 = 1.10 ± 0.12 and 5.15 ± 1.64 μM, respectively) with low cytotoxicity (CC50 ＞ 50 μM). An X-ray co-crystal structure reveals a non-covalent mechanism of action, and a noncanonical binding mode not observed by baicalein. These results suggest that C7 represents a promising lead for development of more effective SARS-CoV-2 Mpro inhibitors and anti-COVID-19 drugs.

Rational Design in Photopharmacology with Molecular Photoswitches.

Photopharmacology is an attractive approach for achieving targeted drug action with the use of light. In photopharmacology, molecular photoswitches are introduced into the structure of biologically active small molecules to allow for the optical control of their potency. Going beyond trial and error, photopharmacology has progressively applied rational drug design methodologies to devise light-controlled bioactive ligands. In this review, we categorize photopharmacological efforts from the standpoint of medicinal chemistry strategies, focusing on diffusible photochromic ligands modified with photoswitches that operate through E-Z bond isomerization. In the vast majority of cases, photoswitchable ligands are designed as analogs of existing compounds, through a variety of approaches. By analyzing in detail a comprehensive list of instructive examples, we describe the state of the art and discuss future opportunities for rational design in photopharmacology.

Rational Design in Photopharmacology with Molecular Photoswitches

AbstractPhotopharmacology is an attractive approach for achieving targeted drug action with the use of light. In photopharmacology, molecular photoswitches are introduced into the structure of biologically active small molecules to allow for the optical control of their potency. Going beyond trial and error, photopharmacology has progressively applied rational drug design methodologies to devise light‐controlled bioactive ligands. In this review, we categorize photopharmacological efforts from the standpoint of medicinal chemistry strategies, focusing on diffusible photochromic ligands modified with photoswitches that operate through E‐Z bond isomerization. In the vast majority of cases, photoswitchable ligands are designed as analogs of existing compounds, through a variety of approaches. By analyzing in detail a comprehensive list of instructive examples, we describe the state of the art and discuss future opportunities for rational design in photopharmacology.

Silicon switch: Carbon-silicon Bioisosteric replacement as a strategy to modulate the selectivity, physicochemical, and drug-like properties in anticancer pharmacophores.

Bioisosterism is one of the leading strategies in medicinal chemistry for the design and modification of drugs, consisting in replacing an atom or a substituent with a different atom or a group with similar chemical properties and an inherent biocompatibility. The objective of such an exercise is to produce a diversity of molecules with similar behavior while enhancing the desire biological and pharmacological properties, without inducing significant changes to the chemical framework. In drug discovery and development, the optimization of the absorption, distribution, metabolism, elimination, and toxicity (ADMETox) profile is of paramount importance. Silicon appears to be the right choice as a carbon isostere because they possess very similar intrinsic properties. However, the replacement of a carbon by a silicon atom in pharmaceuticals has proven to result in improved efficacy and selectivity, while enhancing physicochemical properties and bioavailability. The current review discusses how silicon has been strategically introduced to modulate drug-like properties of anticancer agents, from a molecular design strategy, biological activity, computational modeling, and structure-activity relationships perspectives.

Efecto del compuesto N-2,6-dicloro-aralquil-2-Aminoindano en la conducta estereotipada de ratas. Acción dopaminérgica selectiva central sobre los ganglios basales más que en las estructuras límbicas.

Dopamine 1 is involved in neurodegenerative disorders affect-ing the central nervous system (CNS), such as Parkinson’s disease. Despite the absence of some available drugs capable of preventing, stopping or curing the progression of such diseases, there are numerous compounds designed, synthesized, and pharmacologically tested which give rise to pharmacophoric generalizations about the dopaminergic receptor required for the search of a drug able to improve or cure those pathologies. N-aralkyl-2-aminoindane de-rivatives have shown selective activity in the central dopaminergic system. Both the N-[(2,4-dichlorophenyl)-1-methyl-ethyl]-2-aminoindane hydrochloride 2and N-[(3,4-dichlorophenyl)-1-methyl-ethyl]-2-aminoindane hydrochloride 3 showed an agonistic activity mediated by central dopaminergic mechanisms. To contribute to the search of new drugs able to re-establish homeostasis in the dopaminergic transmission in Parkinson’s disease, the compound N-2,6-dichloro-aralkyl-2-aminoindane 4 was designed through medicinal chemistry strategies that contain pharmacophoric approximations of prodrugs. The phar-macological evaluation of compound 4 in the stereotyped behavior of male Sprague Dawley rats showed agonistic activity through the activation of central dopaminergic mechanisms and a higher selectivity in the responses of stereo-typed behavior characteristic of the basal ganglia over the typical responses from limbic structures.

Synthesis and structure-activity optimization of 7-azaindoles containing aza-β-amino acids targeting the influenza PB2 subunit

The PB2 subunit of influenza virus polymerase has been demonstrated as a promising drug target for anti-influenza therapy. In this work, 7-azaindoles containing aza-β3- or β2,3 -amino acids were synthesized possessing a good binding affinity of PB2. The aza-β-amino acid moieties with diverse size, shape, steric hindrance and configuration were investigated. Then a lead HAA-09 was validated, and the attached aza-β3-amino acid moiety with acyclic tertiary carbon side chain well occupied in the key hydrophobic cavity of PB2_cap binding domain. Importantly, HAA-09 displays potent polymerase inhibition capacity, low cytotoxicity (selectivity index up to 2915) as well as robust anti-viral activity against A/WSN/33 (H1N1) virus and oseltamivir-resistant H275Y variant. Moreover, HAA-09 exhibited druggability with high plasma stability (t1/2 ≥ 12 h) and no obvious hERG inhibition (IC50 > 10 μM). Also, HAA-09 demonstrated a favorable safety profile when orally administrated in healthy mice at a high dose of 40 mg/kg QD for consecutive 3 days. Besides, in vivo therapeutic efficacy (85.7% survival observed at the day 15 post infection) was demonstrated when HAA-09 was administrated orally at 12.5 mg/kg BID starting 48 h post infection for 9 days. These data support that exploring the interactions between side chains on aza-β3- or β2,3 -amino acid moieties and hydrophobic pocket of PB2_cap binding domain is a potential medicinal chemistry strategy for developing potent PB2 inhibitors.

Multipharmacophore strategy in medicinal chemistry for the design of drugs for the treatment of Alzheimer’s and some other neurodegenerative diseases

Multipharmacophore strategy in medicinal chemistry for the design of drugs for the treatment of Alzheimer’s and some other neurodegenerative diseases

Discovery of carboxyl-containing heteroaryldihydropyrimidine derivatives as novel HBV capsid assembly modulators with significantly improved metabolic stability.

Interfering with the assembly of hepatitis B virus (HBV) capsid is a promising approach for treating chronic hepatitis B (CHB). In order to enhance the metabolic stability and reduce the strong hERG inhibitory effect of HBV capsid assembly modulator (CAM) GLS4, we rationally designed a series of carboxyl-containing heteroaryldihydropyrimidine (HAP) derivatives based on structural biology information combined with medicinal chemistry strategies. The results from biological evaluation demonstrated that compound 6a-25 (EC50 = 0.020 μM) exhibited greater potency than the positive drug lamivudine (EC50 = 0.09 μM), and was comparable to the lead compound GLS4 (EC50 = 0.007 μM). Furthermore, it was observed that 6a-25 reduced levels of core protein (Cp) and capsid in cells. Preliminary assessment of drug-likeness revealed that 6a-25 exhibited superior water solubility (pH 2.0: 374.81 μg mL-1; pH 7.0: 6.85 μg mL-1; pH 7.4: 25.48 μg mL-1), liver microsomal metabolic stability (t1/2 = 108.2 min), and lower hERG toxicity (10 μM inhibition rate was 72.66%) compared to the lead compound GLS4. Overall, compound 6a-25 holds promise for further investigation.

Medicinal Chemistry Strategies for the Development of Inhibitors Disrupting β-Catenin's Interactions with Its Nuclear Partners.

Dysregulation of the Wnt/β-catenin signaling pathway is strongly associated with various aspects of cancer, including tumor initiation, proliferation, and metastasis as well as antitumor immunity, and presents a promising opportunity for cancer therapy. Wnt/β-catenin signaling activation increases nuclear dephosphorylated β-catenin levels, resulting in β-catenin binding to TCF and additional cotranscription factors, such as BCL9, CBP, and p300. Therefore, directly disrupting β-catenin's interactions with these nuclear partners holds promise for the effective and selective suppression of the aberrant activation of Wnt/β-catenin signaling. Herein, we summarize recent advances in biochemical techniques and medicinal chemistry strategies used to identify potent peptide-based and small-molecule inhibitors that directly disrupt β-catenin's interactions with its nuclear binding partners. We discuss the challenges involved in developing drug-like inhibitors that target the interactions of β-catenin and its nuclear binding partner into therapeutic agents.

Discovery and Optimization of Indoline-Based Compounds as Dual 5-LOX/sEH Inhibitors: In Vitro and In Vivo Anti-Inflammatory Characterization.

The design of multitarget drugs represents a promising strategy in medicinal chemistry and seems particularly suitable for the discovery of anti-inflammatory drugs. Here, we describe the identification of an indoline-based compound inhibiting both 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH). In silico analysis of an in-house library identified nine compounds as potential 5-LOX inhibitors. Enzymatic and cellular assays revealed the indoline derivative 43 as a notable 5-LOX inhibitor, guiding the design of new analogues. These compounds underwent extensive in vitro investigation revealing dual 5-LOX/sEH inhibitors, with 73 showing the most promising activity (IC50s of 0.41 ± 0.01 and 0.43 ± 0.10 μM for 5-LOX and sEH, respectively). When challenged in vivo in zymosan-induced peritonitis and experimental asthma in mice, compound 73 showed remarkable anti-inflammatory efficacy. These results pave the way for the rational design of 5-LOX/sEH dual inhibitors and for further investigation of their potential use as anti-inflammatory agents.

Advances in AR-targeting chimeras: a case study of proteolysis-targeting chimeras from bench to bedside.

Proteolysis-targeting chimera (PROTAC) is an emerging revolutionary technology that promotes degradation of target proteins by proteolysis. AR-targeting PROTACs marked many milestones in the history of PROTAC development. In this review, the author discusses the development of AR-targeting PROTACs over the last two decades. Also included in this focused review are medicinal chemistry strategies, pharmacokinetic profiles and clinical development. Taking AR targeting PROTACs forcase study, this review provides atarget specific overview of how PROTAC technologyhas advanced from a revolutionary concept and achieved proof of concept leadingto drug candidatesthatbenefitpatients.

Light-Activating PROTACs in Cancer: Chemical Design, Challenges, and Applications

Nonselective cell damage remains a significant limitation of radiation therapies in cancer. Decades of successful integration of radiation therapies with other medicinal chemistry strategies significantly improved therapeutic benefits in cancer. Advancing in such technologies also led to the development of specific photopharmcology-based approaches that improved the cancer cell selectivity and provided researchers with spatiotemporal control over the degradation of highly expressed proteins in cancer (proteolysis targeting chimeras, PROTACs) using a monochrome wavelength light source. Two specific strategies that have achieved notable successes are photocage and photoswitchable PROTACs. Photocaged PROTACs require a photolabile protecting group (PPG) that, when radiated with a specific wavelength of light, irreversibly release PPG and induce protein degradation. Thus far, diethylamino coumarin for estrogen-related receptor α (ERRα), nitropiperonyloxymethyl (BRD4 bromodomain protein), and 4,5-dimethoxy-2-nitrobenzyl for (BRD4 bromodomain protein, as well as BTK kinase protein) were successfully incorporated in photocaged PROTACs. On the other hand, photoswitches of photoswitchable PROTACs act as an actual ON/OFF switch to target specific protein degradation in cancer. The ON/OFF function of photoswitches in PROTACs (as photoswitchable PROTACs) provide spatiotemporal control over protein degradation, and to an extent are correlated with their photoisomeric state (cis/trans-configuration), showcasing an application of the photochemistry concept in precision medicine. This study compiles the photoswitchable PROTACs targeted to bromodomain proteins: BRD 2, 3, and 4; kinases (BCR-ABL fusion protein, ABL); and the immunophilin FKBP12. Photocaging of PROTACs found successes in selective light-controlled degradation of kinase proteins, bromodomain-containing proteins, and estrogen receptors in cancer cells.

Medicinal Chemistry Strategies for the Development of Bruton's Tyrosine Kinase Inhibitors against Resistance.

Despite significant efficacy, one of the major limitations of small-molecule Bruton's tyrosine kinase (BTK) agents is the presence of clinically acquired resistance, which remains a major clinical challenge. This Perspective focuses on medicinal chemistry strategies for the development of BTK small-molecule inhibitors against resistance, including the structure-based design of BTK inhibitors targeting point mutations, e.g., (i) developing noncovalent inhibitors from covalent inhibitors, (ii) avoiding steric hindrance from mutated residues, (iii) making interactions with the mutated residue, (iv) modifying the solvent-accessible region, and (v) developing new scaffolds. Additionally, a comparative analysis of multi-inhibitions of BTK is presented based on cross-comparisons between 2916 unique BTK ligands and 283 other kinases that cover 7108 dual/multiple inhibitions. Finally, targeting the BTK allosteric site and uding proteolysis-targeting chimera (PROTAC) as two potential strategies are addressed briefly, while also illustrating the possibilities and challenges to find novel ligands of BTK.

C−H Methylation Using Sustainable Approaches

C−H methylation of sp2 and sp3 carbon centers is significant in many biological processes. Methylated drug candidates show unique properties due to the change in solubility, conformation and metabolic activities. Several photo-catalyzed, electrochemical, mechanochemical and metal-free techniques that are widely utilized strategies in medicinal chemistry for methylation of arenes and heteroarenes have been covered in this review.

On the Utility of Chemical Strategies to Improve Peptide Gut Stability.

Inherent susceptibility of peptides to enzymatic degradation in the gastrointestinal tract is a key bottleneck in oral peptide drug development. Here, we present a systematic analysis of (i) the gut stability of disulfide-rich peptide scaffolds, orally administered peptide therapeutics, and well-known neuropeptides and (ii) medicinal chemistry strategies to improve peptide gut stability. Among a broad range of studied peptides, cyclotides were the only scaffold class to resist gastrointestinal degradation, even when grafted with non-native sequences. Backbone cyclization, a frequently applied strategy, failed to improve stability in intestinal fluid, but several site-specific alterations proved efficient. This work furthermore highlights the importance of standardized gut stability test conditions and suggests defined protocols to facilitate cross-study comparison. Together, our results provide a comparative overview and framework for the chemical engineering of gut-stable peptides, which should be valuable for the development of orally administered peptide therapeutics and molecular probes targeting receptors within the gastrointestinal tract.

Approaches for discovery of small-molecular antivirals targeting to influenza A virus PB2 subunit

Influenza is an acute respiratory infectious disease caused by influenza virus, leading to huge morbidity and mortality in humans worldwide. Despite the availability of antivirals in the clinic, the emergence of resistant strains calls for antivirals with novel mechanisms of action. The PB2 subunit of the influenza A virus polymerase is a promising target because of its vital role in the ‘cap-snatching’ mechanism. In this review, we summarize the technologies and medicinal chemistry strategies for hit identification, hit-to-lead and lead-to-candidate optimization, and current challenges in PB2 inhibitor development, as well as offering insights for the fight against drug resistance.

Contemporary Medicinal Chemistry Strategies for the Discovery and Development of Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors.

Currently, HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a major component of the highly active anti-retroviral therapy (HAART) regimen. However, the occurrence of drug-resistant strains and adverse reactions after long-term usage have inevitably compromised the clinical application of NNRTIs. Therefore, the development of novel inhibitors with distinct anti-resistance profiles and better pharmacological properties is still an enormous challenge. Herein, we summarize state-of-the-art medicinal chemistry strategies for the discovery of potent NNRTIs, such as structure-based design strategies, contemporary computer-aided drug design, covalent-binding strategies, and the application of multi-target-directed ligands. The strategies described here will facilitate the identification of promising HIV-1 NNRTIs.

Analgesic Opioid Ligand Discovery Based on Nonmorphinan Scaffolds Derived from Natural Sources.

Strong opioid analgesics, including morphine, are the mainstays for treating moderate to severe acute pain and alleviating chronic cancer pain. However, opioid-related adverse effects, including nausea or vomiting, sedation, respiratory depression, constipation, pruritus (itch), analgesic tolerance, and addiction and abuse liability, are problematic. In addition, the use of opioids to relieve chronic noncancer pain is controversial due to the "opioid crisis" characterized by opioid misuse or abuse and escalating unintentional death rates due to respiratory depression. Hence, considerable research internationally has been aimed at the "Holy Grail" of the opioid analgesic field, namely the discovery of novel and safer opioid analgesics with improved opioid-related adverse effects. In this Perspective, medicinal chemistry strategies are addressed, where structurally diverse nonmorphinan-based opioid ligands derived from natural sources were deployed as lead molecules. The current state of play, clinical or experimental status, and novel opioid ligand discovery approaches are elaborated in the context of retaining analgesia with improved safety and reduced adverse effects, especially addiction liability.

Design, Synthesis, and Characterization of I-BET567, a Pan-Bromodomain and Extra Terminal (BET) Bromodomain Oral Candidate

Through regulation of the epigenome, the bromodomain and extra terminal (BET) family of proteins represent important therapeutic targets for the treatment of human disease. Through mimicking the endogenous N-acetyl-lysine group and disrupting the protein-protein interaction between histone tails and the bromodomain, several small molecule pan-BET inhibitors have progressed to oncology clinical trials. This work describes the medicinal chemistry strategy and execution to deliver an orally bioavailable tetrahydroquinoline (THQ) pan-BET candidate. Critical to the success of this endeavor was a potency agnostic analysis of a data set of 1999 THQ BET inhibitors within the GSK collection which enabled identification of appropriate lipophilicity space to deliver compounds with a higher probability of desired oral candidate quality properties. SAR knowledge was leveraged via Free-Wilson analysis within this design space to identify a small group of targets which ultimately delivered I-BET567 (27), a pan-BET candidate inhibitor that demonstrated efficacy in mouse models of oncology and inflammation.

N-1,2,3-Triazole-isatin derivatives: anti-proliferation effects and target identification in solid tumour cell lines.

Molecular hybridization approaches have become an important strategy in medicinal chemistry, and to this end, we have developed a series of novel N-1,2,3-triazole-isatin hybrids that are promising as tumour anti-proliferative agents. Our isatin hybrids presented high cytotoxic activity against colon cancer cell line SW480, lung adenocarcinoma cell line A549, as well as breast cancer cell lines MCF7 and MDA-MB-231. All tested compounds demonstrated better anti-proliferation (to 1-order of magnitude) than the cis-platin (CDDP) benchmark. In order to explore potential biological targets for these compounds, we used information from previous screenings and identified as putative targets the histone acetyltransferase P-300 (EP300) and the acyl-protein thioesterase 2 (LYPLA2), both known to be involved in epigenetic regulation. Advantageous pharmacological properties were predicted for these compounds such as good total surface area of binding to aromatic and hydrophobic units in the enzyme active site. In addition, we found down-regulation of LYPLA2 and EP300 in both the MCF7 and MDA-MB-231 breast cancer cells treated with our inhibitors, but no significant effect was detected in normal breast cells MCF10A. We also observed upregulation of EP300 mRNA expression in the MCF10A cell line for some of these compounds and the same effect for LYPLA2 mRNA in MCF7 for one of our compounds. These results suggest an effect at the transcriptional regulation level and associated with oncological contexts.