Medicinal Chemistry Approaches Research Articles

The Potential Use of Anticancer Peptides (ACPs) in the Treatment of Hepatocellular Carcinoma.

Peptides have acquired increasing interest as promising therapeutics, particularly as anticancer alternatives during recent years. They have been reported to demonstrate incredible anticancer potentials due to their low manufacturing cost, ease of synthesis and great specificity and selectivity. Hepatocellular carcinoma (HCC) is among the leading cause of cancer death globally, and the effectiveness of current liver treatment has turned out to be a critical issue in treating the disease efficiently. Hence, new interventions are being explored for the treatment of hepatocellular carcinoma. Anticancer peptides (ACPs) were first identified as part of the innate immune system of living organisms, demonstrating promising activity against infectious diseases. Differentiated beyond the traditional effort on endogenous human peptides, the discovery of peptide drugs has evolved to rely more on isolation from other natural sources or through the medicinal chemistry approach. Up to the present time, the pharmaceutical industry intends to conduct more clinical trials for the development of peptides as alternative therapy since peptides possess numerous advantages such as high selectivity and efficacy against cancers over normal tissues, as well as a broad spectrum of anticancer activity. In this review, we present an overview of the literature concerning peptide's physicochemical properties and describe the contemporary status of several anticancer peptides currently engaged in clinical trials for the treatment of hepatocellular carcinoma.

Novel analgesic agents obtained by molecular hybridization of orthosteric and allosteric ligands

Despite the high incidence of acute and chronic pain in the general population, the efficacy of currently available medications is unsatisfactory. Insufficient management of pain has a profound impact on the quality of life and can have serious physical, psychological, social, and economic consequences. This unmet need reflects a failure to develop novel classes of analgesic drugs with superior clinical properties and lower risk of abuse. Nevertheless, recent advances in our understanding of the neurobiology of pain are offering new opportunities for developing different therapeutic approaches. Among those, the activation of M2 muscarinic acetylcholine receptors, which play a key role in the cholinergic regulation of the nociceptive transmission, constitutes one of the most promising strategies. We have recently developed a small library of novel pharmacological agents by merging the structures of known orthosteric and allosteric muscarinic ligands through their molecular hybridization, an emerging approach in medicinal chemistry based on the combination of pharmacophoric moieties of different bioactive substances to produce a new compound with improved pharmacological properties. Herein we report the functional characterization of the new ligands in vitro and the assessment of their efficacy as analgesic agents and tolerability in mice. This work provides new insights for the development and optimization of novel muscarinic hybrid compounds for the management of pain.

Esters and amides of 3-R-2,8-dioxo-7,8-dihydro2H-pyrrolo[1,2-a][1,2,4]­triazino[2,3-c]quinazolin-5a(6H)-carboxylic(-propanoic) acids: synthesis and biological activity

It is known that carboxyl groups bonded to aryl or hetaryl moieties play a role of the “pharmacophore” fragment in most NSAID molecules. It should be mentioned that the carboxyl group may cause the appearance of toxic effects and is characterized by unsatisfactory pharmacokinetic properties. The structural modification of the carboxyl group, including its bioisosteric replacement, is among the most widely used approaches in medicinal chemistry to improve pharmacodynamic, pharmacokinetic and technological characteristics.Aim. To develop the synthetic procedures for functional derivatives of 3-R-2,8-dioxo-7,8-dihydro-2Н-pyrrolo[1,2-а][1,2,4]triazino[2,3-с]quinazoline-5а(6Н)-carboxylic(-propanoic) acids, study the effect of the carboxyl group chemical modification on the LOX-inhibiting and antiradical activity as a possible mechanism of the pharmacological activity.Results and discussion. The synthesis of esters of 3-(2,8-dioxo-3-R1-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazolin-5a(6H)-yl)carboxylic(propanoic) acids was conducted by esterification of the corresponding acids and tandem heterocyclization of 2-(6-R1-2,5-dihydro-5-оxo-1,2,4-triazino-3-yl)anilines with diethyl 4-oxoheptanedioate. The synthesis of amides was conducted by aminolysis of N-acylimidazolides generated in situ. The antiradical and LOX-inhibiting activities of the compounds obtained were studied as possible mechanisms of the anti-inflammatory activity. The series of the compounds revealed the LOX-inhibiting activity that was comparable with the effect of the reference compound – nordihydroguaiaretic acid.Experimental part. The synthetic procedures were conducted according to the commonly used methods. The purity and the structure of the compounds obtained were proven by modern physicochemical methods (1H and 13C NMR-spectroscopy, LC-MS-spectrometry). The antiradical activity was measured by the ability to scavenge a DPPH-radical. The study of the LOX-inhibiting activity was performed using soybean LOX as an enzyme and linolenic acid as a substrate.Conclusions. The methods for the synthesis of esters and amides of 2,8-dioxo-3-R1-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazolin-5a(6H)-carboxilic(propanoic) acids have been developed. The abovementioned transformations were conducted by alcoholysis of generated in situ acyl halides and aminolysis of N-acylimidazolides, respectively. The more efficient approach for the synthesis of the target esters via condensation of 2-(6-R1-2,5-dihydro-5-oxo-1,2,4-triazino-3-yl)anilines with diethyl 4-oxoheptanedioate has been proposed. It has been found that the highest radical scavenging and LOX-inhibiting activities are characteristic for hetarylpropanoic acids that contain electron withdrawing substituents in position 3, as well as fluorine atoms in positions 11 and 12. The chemical modification of the carboxylic group in most cases results in a decrease or the loss of the activity. Received: 10.01.2019Revised: 04.02.2020Accepted: 27.02.2020

Targeting Bacterial Cell Division: A Binding Site-Centered Approach to the Most Promising Inhibitors of the Essential Protein FtsZ.

Binary fission is the most common mode of bacterial cell division and is mediated by a multiprotein complex denominated the divisome. The constriction of the Z-ring splits the mother bacterial cell into two daughter cells of the same size. The Z-ring is formed by the polymerization of FtsZ, a bacterial protein homologue of eukaryotic tubulin, and it represents the first step of bacterial cytokinesis. The high grade of conservation of FtsZ in most prokaryotic organisms and its relevance in orchestrating the whole division system make this protein a fascinating target in antibiotic research. Indeed, FtsZ inhibition results in the complete blockage of the division system and, consequently, in a bacteriostatic or a bactericidal effect. Since many papers and reviews already discussed the physiology of FtsZ and its auxiliary proteins, as well as the molecular mechanisms in which they are involved, here, we focus on the discussion of the most compelling FtsZ inhibitors, classified by their main protein binding sites and following a medicinal chemistry approach.

Phenotypic Drug Discovery for Human African Trypanosomiasis: A Powerful Approach.

The work began with the screening of a library of 700,000 small molecules for inhibitors of Trypanosoma brucei growth (a phenotypic screen). The resulting set of 1035 hit compounds was reviewed by a team of medicinal chemists, leading to the nomination of 17 chemically distinct scaffolds for further investigation. The first triage step was the assessment for brain permeability (looking for brain levels at least 20% of plasma levels) in order to optimize the chances of developing candidates for treating late-stage human African trypanosomiasis. Eleven scaffolds subsequently underwent hit-to-lead optimization using standard medicinal chemistry approaches. Over a period of six years in an academic setting, 1539 analogs to the 11 scaffolds were synthesized. Eight scaffolds were discontinued either due to insufficient improvement in antiparasitic activity (5), poor pharmacokinetic properties (2), or a slow (static) antiparasitic activity (1). Three scaffolds were optimized to the point of curing the acute and/or chronic T. brucei infection model in mice. The progress was accomplished without knowledge of the mechanism of action (MOA) for the compounds, although the MOA has been discovered in the interim for one compound series. Studies on the safety and toxicity of the compounds are planned to help select candidates for potential clinical development. This research demonstrates the power of the phenotypic drug discovery approach for neglected tropical diseases.

Systemic delivery of peptides by the oral route: Formulation and medicinal chemistry approaches.

In its 33 years, ADDR has published regularly on the po5tential of oral delivery of biologics especially peptides and proteins. In the intervening period, analysis of the preclinical and clinical trial failures of many purported platform technologies has led to reflection on the true status of the field and reigning in of expectations. Oral formulations of semaglutide, octreotide, and salmon calcitonin have completed Phase III trials, with oral semaglutide being approved by the FDA in 2019. The progress made with oral peptide formulations based on traditional permeation enhancers is against a background of low and variable oral bioavailability values of ~1%, leading to a current perception that only potent peptides with a viable cost of synthesis can be realistically considered. Desirable features of candidates should include a large therapeutic index, some stability in the GI tract, a long elimination half-life, and a relatively low clearance rate. Administration in nanoparticle formats have largely disappointed, with few prototypes reaching clinical trials: insufficient particle loading, lack of controlled release, low epithelial particle uptake, and lack of scalable synthesis being the main reasons for discontinuation. Disruptive technologies based on engineered devices promise improvements, but scale-up and toxicology aspects are issues to address. In parallel, medicinal chemists are synthesizing stable hydrophobic macrocyclic candidate peptides of lower molecular weight and with potential for greater oral bioavailability than linear peptides, but perhaps without the same requirement for elaborate drug delivery systems. In summary, while there have been advances in understanding the limitations of peptides for oral delivery, low membrane permeability, metabolism, and high clearance rates continue to hamper progress.

Abstract A103: Targeting GLI1-mediated NBS1 transcription overcomes 5-FU resistance

Abstract Resistance to radiation and chemotherapy in colorectal patients is considered one of the major contributors of refractory disease and disease progression. Dysregulation or aberrant activation of the SHH/GLI1 signaling pathway, common to both colorectal cancer and other cancer subtypes, influences the integrity of the DNA damage response (DDR) pathway, which may impact tumor response to chemo- and radiation therapies. The DDR pathway is initiated in part by the recognition of a DNA lesion by a sensor protein and the recruitment NBS1 to that lesion. Subsequent repair is initiated by the Mre11, Rad50, NBS1 (MRN) complex formation. In this study, we investigated the expression of GLI1 and NBS1 in tissues samples from 188 patients diagnosed with colorectal cancer by immunohistochemistry and analyzed the clinical significance and prognostic relevance of elevated GLI1-NBS1 co-expression. GLI1 expression was positively associated with the NBS1 expression, and high expression of both in the biopsied specimens significantly correlated with poor patient survival. The result of a series of biochemical experiments directly links GLI1 transcriptional activity to the DNA damage repair pathway. First, NBS1 mRNA levels and protein were found to be reduced upon treatment with GANT61, a GLI inhibitor, indicating that GLI activity was required for NBS1 transcription. Second, overexpression of NBS1 in HT29 cells rescued GANT61-induced cell death by measure of cleaved caspase-3, indicating a significant role of induced DNA damage in the mechanism of GANT61-induced cell death in oncogenic GLI1 cancers. Third, this was verified by ChIP analysis of GLI1 binding to the NBS1 promotor region containing a putative GLI binding sequence. The efficacy of GLI1 inhibition as therapeutic strategy was then tested in parallel with 5-Fluorouracil (5-FU), a component of the standard-of-care therapy FOLFOX. In vitro, colorectal cell lines with GLI1-driven NBS1 expression demonstrated strong 5-FU resistance. These cells were re-sensitized to 5-FU by silencing the expression of NBS1 with siRNA, or with combination therapy involving 5-FU and GANT61. This suggests that a first-in class chemotherapeutic strategy may provide additional treatment options for patients demonstrating 5-FU resistance during the course of their chemotherapy. While GANT61 is commonly used to inhibit GLI in vitro, it exhibits poor pharmacokinetic properties and is not a viable drug for the clinic. To that end, we present a novel GLI1 antagonist SR38832, which exhibits a more stable pharmacokinetic profile than GANT61 in xenograft mouse models and lower IC50 in colon cancer cell lines. In a human colorectal cancer xenograft mouse model, SR38832 significantly inhibited both tumor growth and proliferation. Not only has the identification of SR38832 provided an in vivo tool to study GLI oncogenic activity, but SR38832 is also structural lead to be optimized through an iterative medicinal chemistry approach. Citation Format: Ruowen Zhang, Justin Avery, Jinlu Ma, Theresa Nguyen, Mark J Suto, Bo Xu, Rebecca J Boohaker. Targeting GLI1-mediated NBS1 transcription overcomes 5-FU resistance [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A103. doi:10.1158/1535-7163.TARG-19-A103

Optimization of Ligands Using Focused DNA-Encoded Libraries To Develop a Selective, Cell-Permeable CBX8 Chromodomain Inhibitor

Polycomb repressive complex 1 (PRC1) is critical for mediating gene expression during development. Five chromobox (CBX) homolog proteins, CBX2, CBX4, CBX6, CBX7, and CBX8, are incorporated into PRC1 complexes, where they mediate targeting to trimethylated lysine 27 of histone H3 (H3K27me3) via the N-terminal chromodomain (ChD). Individual CBX paralogs have been implicated as drug targets in cancer; however, high similarities in sequence and structure among the CBX ChDs provide a major obstacle in developing selective CBX ChD inhibitors. Here we report the selection of small, focused, DNA-encoded libraries (DELs) against multiple homologous ChDs to identify modifications to a parental ligand that confer both selectivity and potency for the ChD of CBX8. This on-DNA, medicinal chemistry approach enabled the development of SW2_110A, a selective, cell-permeable inhibitor of the CBX8 ChD. SW2_110A binds CBX8 ChD with a Kd of 800 nM, with minimal 5-fold selectivity for CBX8 ChD over all other CBX paralogs in vitro. SW2_110A specifically inhibits the association of CBX8 with chromatin in cells and inhibits the proliferation of THP1 leukemia cells driven by the MLL-AF9 translocation. In THP1 cells, SW2_110A treatment results in a significant decrease in the expression of MLL-AF9 target genes, including HOXA9, validating the previously established role for CBX8 in MLL-AF9 transcriptional activation, and defining the ChD as necessary for this function. The success of SW2_110A provides great promise for the development of highly selective and cell-permeable probes for the full CBX family. In addition, the approach taken provides a proof-of-principle demonstration of how DELs can be used iteratively for optimization of both ligand potency and selectivity.

Anticancer Molecule Discovery via C2-Substituent Promoted Oxidative Coupling of Indole and Enolate.

SummaryC2, C3-disubstituted indole is one of the most frequently encountered motifs in bioactive alkaloids and medicinal chemistry. Thus, developing novel, concise, and efficient access to it is highly desired in drug discovery. Herein, we present such an approach to this scaffold by direct oxidative coupling of C2-substituted indoles and enolates. Compared with indole bearing no C2-substituent, higher yields (up to 96%) were obtained for C2-substituted indoles in most cases. Mechanistic studies showed the reaction went through a Fe-chelated radical-anion oxidative coupling procedure promoted by C2-substituent on indole by two means: (1) stabilizing C2-radical intermediate during the reaction; (2) reducing indole homocoupling. This approach serves as a synthetic useful tool to quickly build up bioactive small molecule library of C2, C3-disubstituted indoles, and several products showed promising anticancer activities. Besides, indomethacin and its analogs were conveniently prepared in three-step sequence efficiently, indicating the potential application of our approach in medicinal chemistry.

Optimization of the chromone scaffold through QSAR and docking studies: Identification of potent inhibitors of ABCG2

The membrane transporter BCRP/ABCG2 has emerged as a privileged biological target for the development of small compounds capable of abolishing multidrug resistance. In this context, the chromone skeleton was found as an excellent scaffold for the design of ABCG2 inhibitors. With the aims of optimizing and developing more potent modulators of the transporter, we herewith propose a multidisciplinary medicinal chemistry approach performed on this promising scaffold. A quantitative structure-activity relationship (QSAR) study on a series of chromone derivatives was first carried out, giving a robust model that was next applied to the design of 13 novel compounds derived from this nucleus. Two of the most active according to the model’s prediction, namely compounds 22 (5-((3,5-dibromobenzyl)oxy)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide) and 31 (5-((2,4-dibromobenzyl)oxy)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-4-oxo-4H-chromene-2-carboxamide), were synthesized and had their biological potency evaluated by experimental assays, confirming their high inhibitory activity against ABCG2 (experimental EC50 below 0.10 μM). A supplementary docking study was then conducted on the newly designed derivatives, proposing possible binding modes of these novel molecules in the putative ligand-binding site of the transporter and explaining why the two aforementioned compounds exerted the best activity according to biological data. Results from this study are recommended as references for further research in hopes of discovering new potent inhibitors of ABCG2.

Novel antiacanthamoebic compounds belonging to quinazolinones

We report one-pot synthesis of a series of new 3-aryl-8-methylquinazolin-4(3H)-ones (QNZ) and their antimicrobial activity against Acanthamoeba castellanii belonging to T4 genotype. A library of fifteen synthetic derivatives of QNZs was synthesized, and their structural elucidation was performed by using nuclear magnetic resonance (NMR) spectroscopy and electron impact mass spectrometry (EI-MS). Elemental analyses and high-resolution mass spectrometry data of all derivatives were found to be in agreeable range. Amoebicidal assays performed at concentrations ranging from 50 to 100 μg/mL revealed that all derivatives of QNZ significantly decreased the viability of A. castellanii and QNZ 2, 5, 8, and 13 were found to have efficient antiamoebic effects. Field emission scanning electron microscopy (FESEM) imaging of amoeba treated with compounds 5 and 15 showed that these compounds cause structural alterations on the walls of A. castellanii. Furthermore, several QNZs inhibited the encystation and excystationas as well as abolished A. castellanii-mediated host cells cytopathogenicity in human cells. Whereas, these QNZs showed negligible cytotoxicity when tested against human cells in vitro. Hence, this study identified potential lead molecules having promising properties for drug development against A. castellanii. A brief structure-activity relationship is also developed to optimize the hit of most potent compounds from the library. To the best of our knowledge, it is first of its kind medicinal chemistry approach on a single class of compounds i.e., quinazolinone against keratitis and brain infection causing free-living amoeba, A. castellanii.

Abstract 4418: Pharmacological characterization of a preclinical candidate covalently inhibiting CDK12

Abstract Cyclin-dependent kinase 12 (CDK12) is a transcription-associated protein that plays a critical role in DNA damage response, splicing, pre-mRNA processing and is crucial for maintaining genomic stability. CDK12 associated with Cyclin K (CycK) regulates transcription elongation by phosphorylating RNA polymerase II (RNAP II) at Serine 2 (pS2) in the C-terminal domain (CTD). Overexpression of CDK12 in various tumor types suggests the possibility that CDK12 has oncogenic properties, similarly to other transcription-associated kinases. Considering its critical role in transcription and RNA processing, CDK12 is emerging as a potential therapeutic target for cancer. Multiple series of potent and selective CDK12 covalent inhibitors were identified by structure-guided and iterative medicinal chemistry approaches. Early lead compounds were optimized towards achieving high on target potency with good selectivity and desirable drug like properties including pharmacokinetic profile to achieve anti-tumour activity. Optimization of early lead compounds from two distinct chemical series resulted in very potent and highly selective CDK12 covalent inhibitors with desirable oral bioavailability. The covalent mode of action for these biochemically potent compounds has been confirmed by CDK12 target engagement assay in the cellular context. These selective inhibitors showed significant anti-proliferative activity in TNBC and other cancer cell lines including those harbouring ETS fusion. Importantly, cell killing is observed in cancer cells but not in normal cells (RWPE1) with short time (2h) and long-time (72h) exposure of these compounds. Anti-proliferative activity is well correlated with the inhibition of pS2 and down-regulation of a number of DNA damage response genes including BRCA1, RAD51, ATM and FANCI. Consistent with the inhibition of genes involved in DNA damage repair, a highly synergistic anti-proliferative activity was observed when treated in combination with cisplatin and PARP inhibitors. Based on the robust efficacy as a single agent in a TNBC mouse xenograft model with one of the optimized leads, the preclinical candidate exhibiting a greater degree of selectivity is being evaluated for efficacy and tolerability in relevant preclinical models. Citation Format: Ramulu Poddutoori, Sujatha Rajagopalan, Subhendu Mukherjee, Sivapriya Marappan, Samiulla D. S., Sasirekha Sivakumar, Shilpa S Nayak, Ravindra M V, Devaraja TS, Srinivas Kondela, Suraj Tgore, Amit A Dhudashiya, Charamanna K. B, Aravind A B, Amith A, Pavithra S, Hema Sankar Pathange, Thomas Antony, Mahaboobi Jaleel, Sanjeev Giri, Girish Daginakatte, Kavitha Nellore, Shekar Chelur, Murali Ramachandra, Susanta Samajdar. Pharmacological characterization of a preclinical candidate covalently inhibiting CDK12 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4418.

Synthesis of Indoles through Domino Reactions of 2‐Fluorotoluenes and Nitriles

AbstractIndoles are essential heterocycles in medicinal chemistry, and therefore, novel and efficient approaches to their synthesis are in high demand. Among indoles, 2‐aryl indoles have been described as privileged scaffolds. Advanced herein is a straightforward, practical, and transition‐metal‐free assembly of 2‐aryl indoles. Simply combining readily available 2‐fluorotoluenes, nitriles, LiN(SiMe3)2, and CsF enables the generation of a diverse array of indoles (38 examples, 48–92 % yield). A range of substituents can be introduced into each position of the indole backbone (C4 to C7, and aryl groups at C2), providing handles for further elaboration.

Discovery of Peptide Antibiotics Composed of d-Amino Acids.

A paucity of viable programs and pipelines for the discovery of new antibiotics poses a significant public health threat. The emergence of resistant strains against vancomycin is particularly dangerous in hospital settings. Here, we report the design of enantiomeric targets based on bacterial cell wall biosynthesis precursors that allow for selection and identification of short linear, cyclic and bicyclic peptides that are composed of d-amino acids. These compounds are active against Staphylococcus aureus, Methicillin-resistant S. aureus, and vancomycin-resistant Enterococci that possess moderately high antibacterial activity and furthermore display no toxicity to both human red blood cells and mammalian cells at these concentrations. This 'mirror image phage display' approach yielded templates that can serve as scaffolds for further improvements in activity-based structural modifications. This strategy has the potential to provide a new class of antimicrobials that are metabolically stable and have the promise for oral delivery. The use of this platform combined with traditional medicinal chemistry approaches could rapidly yield large numbers of new therapeutic lead compounds.

Structure-Aided Identification and Optimization of Tetrahydro-isoquinolines as Novel PDE4 Inhibitors Leading to Discovery of an Effective Antipsoriasis Agent.

Psoriasis is a common, chronic inflammatory disease characterized by abnormal skin plaques, and the effectiveness of phosphodiesterase 4 (PDE4) inhibitor to lessen the symptoms of psoriasis has been proved. Aiming to find a novel PDE4 inhibitor acting as an effective, safe, and convenient therapeutic agent, we constructed a library consisting of berberine analogues, and compound 2 with a tetrahydroisoquinoline scaffold was identified as a novel and potent hit. The structure-aided and cell-based structure-activity relationship studies on a series of tetrahydro-isoquinolines lead to efficient discovery of a qualified lead compound (16) with the high potency and selectivity, well-characterized binding mechanism, high cell permeability, good safety and pharmacokinetic profile, and impressive in vivo efficacy on antipsoriasis, in particular with a topical application. Thus, our study presents a prime example for efficient discovery of novel, potent lead compounds derived from natural products using a combination of medicinal chemistry, biochemical, biophysical, and pharmacological approaches.

Studies on Isoniazid Derivatives through a Medicinal Chemistry Approach for the Identification of New Inhibitors of Urease and Inflammatory Markers

A library of thiosemicarbazide derivatives of isoniazid 3–27, was synthesized and evaluated for their anti-inflammatory and urease inhibition activities, by using in vitro bioassays. Among these compounds 9, 10, 12, 21, and 26 were identified as new derivatives. Prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs) and infections caused by Helicobacter pylori (ureolytic bacteria), are the two most significant causes of gastric and peptic ulcers. We focused on the identification of the dual inhibitors of inflammation and urease enzyme. Compound 23 was identified as the best dual inhibitor of inflammation (ROS; IC50 = 12.3 µg/mL), and urease enzyme inhibition activity (IC50 = 22.4 µM). Many of these compounds showed comparable activities to the standard anti-inflammatory drug (ibuprofen, IC50 = 11.2 µg/mL) and urease inhibitor (thiourea/acetohydraoxamic acid, IC50 = 21.1/20.3 µM). Compound 12 was found to be the most potent urease inhibitor (IC50 = 12.3 µM) and good inhibitor of inflammation (IC50 = 27.7 µg/mL). Compounds 19, 11, 13, 9, 17, 10, and 16, were also found to be potent inhibitors of urease. Cytotoxicity was also evaluated and all the compounds were found to be non-cytotoxic, except compound 18 and the parent drug isoniazid (IC50 = 29.5 and 28.5 µM, respectively).

Discovery of Small Molecule Renal Outer Medullary Potassium (ROMK) Channel Inhibitors: A Brief History of Medicinal Chemistry Approaches To Develop Novel Diuretic Therapeutics.

The renal outer medullary potassium (ROMK) channel is a member of the inwardly rectifying family of potassium (Kir, Kir1.1) channels. It is primarily expressed in two regions of the kidney, the cortical collecting duct (CCD) and the thick ascending loop of Henle (TALH). At the CCD it tightly regulates potassium secretion while controlling potassium recycling in TALH. As loss-of-function mutations lead to salt wasting and low blood pressure, it has been surmised that inhibitors of ROMK would represent a target for new and improved diuretics for the treatment of hypertension and heart failure. In this review, we discuss and provide an overview of the medicinal chemistry approaches toward the development of small molecule ROMK inhibitors over the past decade.

Prediction of Drug-Drug Interactions Related to Inhibition or Induction of Drug-Metabolizing Enzymes.

Drug-drug interaction (DDI) is the phenomenon of alteration of the pharmacological activity of a drug(s) when another drug(s) is co-administered in cases of so-called polypharmacy. There are three types of DDIs: pharmacokinetic (PK), pharmacodynamic, and pharmaceutical. PK is the most frequent type of DDI, which often appears as a result of the inhibition or induction of drug-metabolising enzymes (DME). In this review, we summarise in silico methods that may be applied for the prediction of the inhibition or induction of DMEs and describe appropriate computational methods for DDI prediction, showing the current situation and perspectives of these approaches in medicinal and pharmaceutical chemistry. We review sources of information on DDI, which can be used in pharmaceutical investigations and medicinal practice and/or for the creation of computational models. The problem of the inaccuracy and redundancy of these data are discussed. We provide information on the state-of-the-art physiologically- based pharmacokinetic modelling (PBPK) approaches and DME-based in silico methods. In the section on ligand-based methods, we describe pharmacophore models, molecular field analysis, quantitative structure-activity relationships (QSAR), and similarity analysis applied to the prediction of DDI related to the inhibition or induction of DME. In conclusion, we discuss the problems of DDI severity assessment, mention factors that influence severity, and highlight the issues, perspectives and practical using of in silico methods.

Engineering Atypical Tetracycline Formation in Amycolatopsis sulphurea for the Production of Modified Chelocardin Antibiotics.

To combat the increasing spread of antimicrobial resistance and the shortage of novel anti-infectives, one strategy for the development of new antibiotics is to optimize known chemical scaffolds. Here, we focus on the biosynthetic engineering of Amycolatopsis sulphurea for derivatization of the atypical tetracycline chelocardin and its potent broad-spectrum derivative 2-carboxamido-2-deacetyl-chelocardin. Heterologous biosynthetic genes were introduced into this chelocardin producer to modify functional groups and generate new derivatives. We demonstrate cooperation of chelocardin polyketide synthase with tailoring enzymes involved in biosynthesis of oxytetracycline from Streptomyces rimosus. An interesting feature of chelocardin, compared with oxytetracycline, is the opposite stereochemistry of the C4 amino group. Genes involved in C4 transamination and N,N-dimethylation of oxytetracycline were heterologously expressed in an A. sulphurea mutant lacking C4-aminotransferase. Chelocardin derivatives with opposite stereochemistry of the C4 amino group, as N,N-dimethyl- epi-chelocardin and N,N-dimethyl-2-carboxamido-2-deacetyl- epi-chelocardin, were produced only when the aminotransferase from oxytetracycline was coexpressed with the N-methyltransferase OxyT. Surprisingly, OxyT exclusively accepted intermediates carrying an S-configured amino group at C4 in chelocardin. Applying medicinal chemistry approaches, several 2-carboxamido-2-deacetyl- epi-chelocardin derivatives modified at C4 were produced. Analysis of the antimicrobial activities of the modified compounds demonstrated that the primary amine in the R configuration is a crucial structural feature for activity of chelocardin. Unexpectedly, C10 glycosylated chelocardin analogues were identified, thus revealing the glycosylation potential of A. sulphurea. However, efficient glycosylation of the chelocardin backbone occurred only after engineering of a dimethylated amino group at the C4 position in the opposite S configuration, which suggests some evolutionary remains of chelocardin glycosylation.

Anti-cholinesterase hybrids as multi-target-directed ligands against Alzheimer’s disease (1998–2018)

Alzheimer's disease (AD) is a genetically complex, progressive and irreversible neurodegenerative disorder of the brain which involves multiple associated etiological targets. The complex pathogenesis of AD gave rise to multi-target-directed ligands (MTDLs) principle to combat this dreaded disease. Within this approach, the design and synthesis of hybrids prevailed greatly because of their capability to simultaneously target the intertwined pathogenesis components of the disease. The hybrids include pharmacophoric hybridization of two or more established chemical scaffolds endowed with the desired pharmacological properties into a single moiety. In AD, the primary foundation of medication therapy and drug design strategies includes the inhibition of cholinesterase (ChE) enzymes. Hence the development of ChE inhibition based hybrids is the central choice of AD medicinal chemistry research. To illustrate the progress of ChE inhibition based hybrids and novel targets, we reviewed the medicinal chemistry and pharmacological properties of the multi-target molecules published since 1998-December 2018. We hope that this article will allow the readers to easily follow the evolution of this prominent medicinal chemistry approach to develop a more efficient inhibitor.