Medicinal Chemistry Research Articles

In Silico and In Vitro Investigation of Cytotoxicity and Apoptosis of Acridine/Sulfonamide Hybrids Targeting Topoisomerases I and II

Background: Sulfonamide acridine derivatives have garnered significant attention from medicinal chemists due to their diverse range of biological activities. Methods: In this study, eleven compounds were synthesized according to the literature, and their impact on cell growth inhibition, induction of apoptosis, and cell cycle distribution were assessed in three different cell lines. Their inhibitory effects on the topoisomerase (Topo) I and II were investigated in vitro. Molecular docking studies were conducted to predict the binding affinities of these compounds for crystallized downloaded topoisomerases. Results: The compounds were examined in vitro for their anticancer activity against human hepatic (HepG2) colon (HCT-8) and breast (MCF-7) carcinoma cell lines. Compound 8b was the most active against HepG2, HCT-116, and MCF-7 with IC50 14.51, 9.39, and 8.83 µM, respectively, compared to Doxorubicin as reference. In addition, it demonstrated the highest potency among the tested compounds against Topo-I, with an IC50 value of 3.41 µg/mL compared to the control camptothecin (IC50 of 1.46 μM). Compound 7c displayed a significant inhibitory effect on Topo-II, with an IC50 of 7.33 μM, compared to an IC50 value of 6.49 μM via Doxorubicin, the control. Compounds 7c and 8b were assessed against topoisomerases showing induction of apoptosis and a reduction in the S phase of the cell cycle. Molecular docking demonstrated interaction with the active site as with those exhibited by the co-crystallized ligands of the crystallized proteins in both topoisomerases. Conclusion: Compounds 7c and 8b hold promise as potential anticancer drugs due to their anti-proliferative and proapoptotic effects, which are mediated by their action on the topoisomerase enzyme, particularly Topo II.

Unveiling tomorrow: Carbonic anhydrase activators and inhibitors pioneering new frontiers in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder and a principal basis of dementia in the elderly population globally. Recently, human carbonic anhydrases (hCAs, EC 4.2.1.1) were demonstrated as possible new targets for treating AD. hCAs are vital for maintaining pH balance and performing other physiological processes as they catalyze the reversible hydration of carbon dioxide to bicarbonate and a proton. Current research indicates that hCA plays a role in brain functions critical for transmitting neural signals. Activation of carbonic anhydrase (CA) has emerged as a promising avenue in addressing memory loss and cognitive issues. Conversely, the exploration of CA inhibition represents a novel frontier in this field. By enhancing glial fitness and cerebrovascular health and blocking amyloid-β (Aβ)-induced mitochondrial dysfunction pathways, cytochrome C (CytC) release, caspase 9 activation, and H2O2 generation in neurons, CA inhibitors improve cognition and lessen the pathology caused by Aβ. Recent research has pushed hCAs into the spotlight as critical players in AD pathogenesis and precise therapeutic targets. The captivating dilemma of choosing between hCA inhibitors and activators looms large, as inhibitors reduce Aβ aggregation and improve cerebral blood flow, while activators enhance cerebrovascular functions and restore pH balance. The current review sheds light on the clinical evidence for hCAs and the roles of inhibitors and activators in AD. Additionally, this review offers a fascinating outlook on the data that may aid medicinal chemists in designing and developing new leads that are more effective and selective for upcoming in vitro and in vivo studies, allowing for the discovery and introduction of novel drug candidates for the treatment of AD to the market and into the clinical pipeline.

Anticancer Potential of Piperidine Containing Small Molecule Targeted Therapeutics

AbstractIn the past two decades, targeted anti‐cancer therapeutics have achieved remarkable success due to their exceptional advantages of selectivity towards cancer cells and safety. Targeted small molecule anti‐cancer therapies persisted in many barriers; majorly poor response to drug therapy. Piperidine, a heterocyclic moiety, exceeds twenty instances of other pharmaceutical classes and natural compounds in the form of alkaloids effective in anti‐cancer treatment. The current review focuses on recent advancements, mainly from 2017–2023, of piperidine‐containing small molecule development as anti‐cancer agents. Total 10 piperidine containing anti‐cancer drugs have been approved by USFDA since 2017 to till date and around 15 small molecule anti‐cancer inhibitors containing piperidine scaffold which are in their early discovery phase have been reviewed which are classified according to their biological target. It highlights the structural contribution of piperidine ring towards the enhancement of activity or pharmacokinetic properties of diverse biological target‐specific anti‐cancer inhibitors of angiogenesis, EGFR, VEGFR, ALK, AKT1, topoisomerase, CDK2 etc. The role of the piperidine ring in enhancing potency, selectivity and bioavailability of novel molecules has been discussed. This review will be helpful to researchers, especially medicinal chemists, for the designing of piperidine‐containing potent drugs for specific biological targets for cancer.

Electrochemical Investigation of Symmetric Aminoquinones

Abstract Quinones have a wide range of valuable properties and potential applications in medicinal chemistry, materials science, optoelectronic devices, and batteries. Molecular redesign using different functional groups, like amines, can optimize their properties and prevent undesired side reactions. However, the synthesis of aminoquinones can be particularly challenging at times, and there is a need for simple and efficient routes to access these compounds without metal catalysts or halogenated starting materials. Here, we demonstrate the synthesis and electrochemical characterization of a series of aminoquinones derived from renewable sources, namely vanillin or 2-methoxyhydroquinone. We employ a series of primary and secondary amines, varying in their electronic situation as well as steric demand. Depending on the type of starting material, either the desired aminoquinone or the related Schiff-base adduct was obtained. The aminoquinones were further explored towards their stability at different pH values. At extreme pH values, the deeply colored aminoquinones decompose, accompanied by decolorization of the solutions within a few minutes (pH 14) or hours (pH 1). At intermediate pH values (3-8) the aminoquinones are stable upon storage in solution, where they feature a quasi-reversible redox chemistry and fast, diffusion limited kinetics.

Bee venom and melittin: Potent key enzyme inhibitors with promising therapeutic potential

Bee venom (BV) is a versatile product with extensive applications, boasting antibacterial and anticancer properties. Within this study, we focused on isolating melittin (Mel) from Apis mellifera L. venom and exploring the influence of both BV and Mel on specific enzymes, namely carbonic anhydrase (CA) I, CA II, CA IX, glutathione reductase (GR), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and neuraminidase (NA). The rationale for selecting these enzymes is that their inhibitors have a particular interest in medicinal chemistry in the treatment of several diseases. BV was obtained using a poison collection apparatus, and Mel was isolated by means of High-Performance Liquid Chromatography (HPLC). All enzymes, except for CA I and CA II, were commercially sourced and of high purity, and the enzyme assays were carried out spectrophotometrically.Our findings showed that BV inhibited the enzymes with IC50 values of 0.583–3.32 ng/mL, and Mel showed an inhibition range of 0.528–3.2 ng/mL. These results underscore the potential therapeutic promise of BV and Mel as robust enzyme inhibitors, offering prospects for addressing diverse health conditions.

Discovery of CRBN-Dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library.

Small molecules promoting protein-protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While cereblon molecular glue degraders containing glutarimide scaffolds have been approved for treatment of multiple myeloma and acute myeloid leukemia, the design of new therapeutically relevant monovalent degraders remains challenging. We report here an approach to glutarimide-containing molecular glue synthesis using multicomponent reactions as a central modular core-forming step. Screening the resulting library identified HRZ-1 derivatives that target casein kinase 1 α (CK1α) and Wee-like protein kinase (WEE1). Further medicinal chemistry efforts led to identification of selective monovalent WEE1 degraders that provide a potential starting point for the eventual development of a selective chemical degrader probe. The structure of the hit WEE1 degrader complex with CRBN-DDB1 and WEE1 provides a model of the protein-protein interface and ideas to rationalize the observed kinase selectivity. Our findings suggest that modular synthetic routes combined with in-depth structural characterization give access to selective molecular glue degraders and expansion of the CRBN-degradable proteome.

Targeting N-methyl-lysine histone demethylase KDM4 in cancer: natural products inhibitors as a driving force for epigenetic drug discovery.

KDM4A-F enzymes are a subfamily of histone demethylases containing the Jumonji C domain (JmjC) using Fe(II) and 2-oxoglutarate for their catalytic function. KDM4 enzymes are overexpressed or deregulated in cancer, thus leading to alteration in chromatin structure and transcriptional defects. As KDM4 enzymes have been associated with malignancy, they may represent novel targets for developing innovative therapeutic tools to treat different solid and blood tumors, of note, KDM4A is the isozyme most frequently associated with aggressive phenotypes of these tumors. To this aim, industrial and academic medicinal chemistry efforts have identified different KDM4 inhibitors. In most cases, these are pan-KDM4 inhibitors, with low selectivity against other Jumonji family members. The pharmacophoric features of the inhibitors frequently include a chelating group capable of coordinating the catalytic iron within the active site of the KDM4 enzyme. Nonetheless, non-chelating compounds have also demonstrated promising inhibitory activity, suggesting potential flexibility in the drug design. Several natural products, containing monovalent or bivalent chelators, have been identified as KDM4 inhibitors, albeit with a micromolar inhibition potency. This highlights the potential for leveraging them as templates for the design and synthesis of new derivatives, exploiting nature's chemical diversity to pursue more potent and selective KDM4 inhibitors.

Based on magnetically recoverable catalysts: a green strategy to sulfonamides.

The synthesis of sulfonamides, a class of compounds with significant pharmaceutical and medicinal applications, has seen remarkable advancements with the advent of magnetic nanocatalysts. Magnetic nanocomposites are one of the most efficient and widely used catalysts, and they are in complete harmony with the principles of modern green chemistry from the point of view of catalysis. These catalysts, typically composed of metal complexes supported on magnetic nanoparticles, offer unique advantages such as ease of recovery and reusability, which are crucial for sustainable and eco-friendly chemical processes. This review comprehensively examines recent developments in applying magnetic nanocatalysts to prepare sulfonamides. Key focus areas include the design and synthesis of various magnetic nanocatalysts (MNC), their catalytic performance in different reaction conditions, and mechanistic insights into their catalytic activity. By summarizing the latest research and technological advancements, this article aims to provide a valuable resource for researchers and practitioners in catalysis and pharmaceutical chemistry.

Trimethyl Lock Based Tools for Drug Delivery and Cell Imaging - Synthesis and Properties.

Trimethyl lock (TML) systems have become increasingly important in medicinal and bioorganic chemistry, particularly for their roles in the targeted delivery of therapeutic agents and as integral components in fluorogenic probes for cellular imaging. The simplicity and efficiency of their synthesis have established TML systems as versatile platforms for the controlled release of active molecules under particular physiological conditions. This review consolidates recent advancements in the application of TML systems, with a focus on their use in drug delivery, cellular imaging, and other areas where precise molecular release is crucial. Additionally, we discuss the synthetic strategies employed to construct TML-based conjugates, underscoring their potential to enhance the specificity and efficacy of bioactive compounds in various biomedical applications.

In memory of an exquisite medicinal chemist, Prof. Morris Robins

Among the most prominent realizations of Morris J. Robins in the antiviral nucleoside chemistry are (i) the synthesis of 8-substituted (methyl-, amino-, bromo-, iodo) derivatives of acyclovir, (ii) xylotubercidin as an inhibitor of herpes simplex virus (HSV) infections, (iii) the anti-HIV activity of the 2’,3’-dideoxyriboside of 2,6-diaminopurine (ddDAPR) and the 3’-azido- and 3’-fluoro derivatives thereof (AzddDAPR and FddDAPR, respectively), (iv) the potentiating effect of ribavirin on the anti-HIV activity of 2’,3’-dideoxyinosine (ddI) and ddDAPR, (v) S-adenosylhomocysteine hydrolase (SAH) inhibitors principally active against vaccinia virus (VV) and vesicular stomatitis virus (VSV), and (vi) furo[2,3-d]pyrimidinone derivatives active against varicella-zoster virus (VZV).

A Comprehensive Review on the Synthesis of Mangiferin Derivatives and their Multiple Biological Activities

Mangiferin always draws the attention of traditional as well as modern medicinal chemists because of its ease of chemical derivatization and diverse biological activities, including anticancer, anti-inflammatory, neuroprotective, antidiabetic, analgesic, antimalarial, anticonvulsant, laxative, cardiotonic, hemopoietic, antioxidant, antimicrobial, antipsychotic, anticoagulant, and antihypertensive properties. This review focuses on a detailed and updated overview of the synthesis of mangiferin derivatives and their diverse biological activities, with examples from both patented and non-patented literature.

Screening and design of PARP12 inhibitors from traditional Chinese medicine small molecules using computational modeling and simulation

The poly (ADP-ribose) polymerase (PARP) family of enzymes plays a pivotal role in orchestrating a multitude of cellular processes, including DNA repair mechanisms, transcriptional regulation, and modulation of immune responses. Within this family, PARP12 emerges as a noteworthy candidate for targeted cancer therapeutics. Consequently, this investigation endeavors to screen and design potential PARP12 inhibitors derived from traditional Chinese medicinal compounds by employing sophisticated molecular modeling and computational medicinal chemistry approaches. The compound RBN2397 is utilized as a benchmark, and the binding efficacies of the newly identified small molecules are assessed against a spectrum of criteria, encompassing molecular interactions, binding free energy, and extensive post-simulation analyses. The outcomes demonstrated that the identified small molecules, specifically tcm8650 and its derivative XC-1, possess remarkable binding affinities and exhibit reduced binding free energies compared to RBN2397. The molecular docking and interaction profiles of these compounds were also comprehensively scrutinized. Moreover, ADMET profiling meticulously evaluated the pharmacokinetic profiles and physicochemical characteristics of these promising molecules and their projected human physiological impact. These computational studies indicated their potential therapeutic applicability and predicted acceptable safety profile, advocating their further exploration as viable candidates in cancer treatment.

Aniline Derivatives Containing 1-Substituted 1,2,3-Triazole System as Potential Drug Candidates: Pharmacokinetic Profile Prediction, Lipophilicity Analysis Using Experimental and In Silico Studies

Background: The triazole ring is an attractive structural unit in medicinal chemistry, and chemical compounds containing this type of system in their structure exhibit a wide spectrum of biological activity. They are used in the development of new pharmaceuticals. One of the basic parameters considered in the initial phase of designing potential drugs is lipophilicity, which affects the bioavailability and pharmacokinetics of drugs. Methods: The study aimed to assess the lipophilicity of fifteen new triazole derivatives of aniline using reversed phase thin layer chromatography (RP-TLC) and free web servers. Based on in silico methods, the drug similarity and pharmacokinetic profile (ADMET) of synthesized molecules were assessed. Results: A relationship was observed between the structure of the title compound, including the position of substitution in the aniline ring, and the experimental values of lipophilicity parameters (logPTLC). Most of the algorithms used to determine theoretical logP values showed less sensitivity to structural differences of the tested molecules. All obtained derivatives satisfy the drug similarity rules formulated by Lipinski, Ghose and Veber. Moreover, in silico analysis of the ADME profile showed favorable values of parameters related to absorption.

Green synthesis of benzimidazole derivatives using copper(II)-supported on alginate hydrogel beads

The study addresses the challenge of developing sustainable and efficient catalytic systems for the synthesis of benzimidazole derivatives, which are of significant importance in the field of medicinal chemistry due to their diverse biological activities. The objective is to develop a recyclable and environmentally friendly catalyst utilizing copper(II)-loaded alginate hydrogel beads, which can facilitate the synthesis of these compounds while minimizing environmental impact. The preparation process entails crosslinking sodium alginate with copper(II) ions to form hydrogel beads, which are then washed and characterized through techniques such as scanning electron microscopy (SEM), Energy dispersive X-ray spectroscopy (EDX), Fourier Transform Infrared Spectroscopy (FTIR), X-ray diffraction (XRD), Inductively coupled plasma (ICP), and Zeta potential to analyses the morphology, composition and porosity of the beads. The catalytic performance is evaluated through recycling tests, which demonstrate the catalyst's ability to maintain selectivity and activity over multiple reaction cycles. The Cu(II)-Alg hydrogel beads were used for synthesizing substituted benzimidazole derivatives in a water-ethanol solvent at room temperature. This method offers significant advantages, including extremely mild reaction conditions, short reaction times (<1 h), high yields (70–94 %), and ease of processing. The most significant results indicate that the Cu(II)-alginate catalyst exhibits a high loading capacity and retains its catalytic efficiency for at least 3 cycles, thereby highlighting its potential for sustainable applications in organic synthesis.

Green Synthetic Methods of Oxazine and Thiazine Scaffolds as Promising Medicinal Compounds: A Mini-review.

Medical researchers have paid close attention to the green synthesis of oxazine and thiazine derivatives since they provided a lead molecule for the creation of numerous possible bioactive compounds. This review provides more information on green synthesis, which will be very helpful to researchers in creating the most effective, affordable, and clinically significant thiazine and oxazine derivatives that are anticipated to have strong pharmacological effects. This has resulted in the identification of several substances with a wide range of intriguing biological functions. This article's goal is to examine the numerous green chemical processes used to create oxazine and thiazine derivatives and their biological activity. We anticipate that researchers interested in oxazine and thiazine chemicals will find this material to be useful. We anticipate that medicinal chemists looking for new active medicinal components for drug discovery and advance progress will find this review of considerable interest.

1,3,4-Oxadiazole: An Emerging Scaffold to Inhibit the Thymidine Phosphorylase as an Anticancer Agent.

Thymidine phosphorylase (TP), also referred to as "platelet-derived endothelial cell growth factor" is crucial to the pyrimidine salvage pathway. TP reversibly transforms thymidine into thymine and 2-deoxy-D-ribose-1-phosphate (dRib-1-P), which further degraded to 2-Deoxy-D-ribose (2DDR), which has both angiogenic and chemotactic activity. In several types of human cancer such as breast and colorectal malignancies, TP is abundantly expressed in response to biological disturbances like hypoxia, acidosis, chemotherapy, and radiation therapy. TP overexpression is highly associated with angiogenic factors such as vascular endothelial growth factor (VEGF), interleukins (ILs), matrix metalloproteases (MMPs), etc., which accelerate tumorigenesis, invasion, metastasis, immune response evasion, and resistant to apoptosis. Hence, TP is recognized as a key target for the development of new anticancer drugs. Heterocycles are the primary structural element of most chemotherapeutics. Even 75% of nitrogen-containing heterocyclic compounds are contributing to the pharmaceutical world. To create the bioactive molecule, medicinal chemists are concentrating on nitrogen-containing heterocyclic compounds such as pyrrole, pyrrolidine, pyridine, imidazole, pyrimidines, pyrazole, indole, quinoline, oxadiazole, benzimidazole, etc. The Oxadiazole motif stands out among all of them due to its enormous significance in medicinal chemistry. The main thrust area of this review is to explore the synthesis, SAR, and the significant role of 1,3,4-oxadiazole derivatives as a TP inhibitor for their chemotherapeutic effects.

An Overview on Antifilarial Efficacy of Heterocyclic Motifs Encompassing Synthetic Strategies, SAR, and Commercialized Medications.

Filariasis is one of the oldest, most dangerous, debilitating, disfiguring diseases and often ignores tropical disorders. It presents with a range of clinical symptoms, a low death rate, and a high morbidity rate, which contributes to social discrimination. This condition has major effects on people's socioeconomic circumstances. This illness is carried by mosquitoes that have spread malaria. Lymphatic filariasis, caused by Wuchereria bancrofti, Brugia malayi, and Brugia timori, is a crippling illness with serious social and economic consequences. The infection persisted despite therapy with conventional antifilarial medications such as diethylcarbamazine (DEC), albendazole, and ivermectin, which are mostly microfilaricides. Current treatments (ivermectin, diethylcarbamazine, and albendazole) have limited effectiveness against adult parasites and produce side effects; therefore, innovative antifilarial medications are urgently required. Hence, macrofilaricides, embryostatic agents, and improved microfilaricides are required. The following article discusses the typical synthetic methodologies established for antifilarial activity as well as their marketed pharmaceuticals, which will help researchers, medicinal chemists, and pharmaceutical scientists to develop new and effective antifilarial therapies. This review can help to identify new lead compounds and optimize existing commercial medications to improve their therapeutic efficacy. The majority of the studies addressed in this review concern the forms of filariasis, parasite life cycle, symptoms, medications used to treat filariasis, synthetic schemes, SAR, and results from the reported research.

Formal synthesis of ferruginol methyl ether via an acid-catalysed intramolecular Diels-Alder cycloaddition

Aromatic abietane diterpenoids, known for their wide range of biological and pharmaceutical activities, have attracted considerable interest from synthetic and medicinal chemists. Although some aromatic abietane diterpenoids are naturally abundant, many are only available in limited quantities, constraining their use in detailed biological investigations. We initiated a project to synthesize these compounds, and as our first approach, we describe the formal synthesis of ferruginol methyl ether. Starting from tiglic aldehyde (6) and 2-bromo-5-methoxybenzoic acid (11), we synthesized the triene (3) in nine steps. The key transformation involved an acid-catalysed intramolecular Diels-Alder (IMDA) cyclisation of triene (3), leading to the formation of 12-methoxy-19-norpodocarpa-4(18),8,11,13-tetraene (14) as the primary product, with an overall yield of 17.3 % across ten steps. While the yield is modest, this approach provides a novel pathway for synthesizing abietane-type compounds. We are actively exploring strategies to improve the overall yield and developing an asymmetric synthesis variant.

Azole Derivatives: Cutting‐Edge Agents in Cancer Therapy

AbstractMonocyclic 5‐membered heterocycles including imidazoles, thiazoles, oxazoles, and their related compounds have gained significant attention in medicinal chemistry because of their potent anticancerous activity. These small heterocyclic molecules possess versatile properties, including biological activity, absorption, distribution, metabolism, excretion, and chemical diversity that give them immense potential as anticancer agents. It is also a fact that inherent characteristic of azoles to combine with many biological molecules through hydrogen bond, stacking, and hydrophobic interaction makes them effective against almost all cancer types. In the present paper the author discusses the way which is connected with chemical structure of monocyclic azoles and their anticancer activity namely the ability of these compounds to intercalate with DNA, to inhibit some enzymes and to interfere cellular signaling pathways. Interestingly, several azole derivatives have been seen to be effective in preclinical efficacy studies as well as in clinical trials and are considered to be potent in overcoming the problem of resistance and side effects of the common anticancer agents. As the synthetic chemistry progresses, the structural system of the azoles has diversified and development in the pharmacology has become more specific. This has helped in enhancing the formation of new molecules in the azole class with improved selectivity and efficacy. Furthermore, the comprehensive review explains how computational chemistry and structure‐activity relationship (SAR) approaches are applied to the design of future‐generation azole compounds. In light of these facts, this article is designed to give a broad overview of the current state of monocyclic azole‐based anticancer agents in an attempt to further assert its therapeutic promise and spur further attempts at infusing the said agents into the cancer therapeutics fray. The discoveries made in this study may allow the development the radical different therapeutic approaches, which could lead to improved and targeted treatment of cancer.

Photoredox-Catalyzed Three-Component Construction of Aryl Sulfonyl Fluoride Using KHF2: Late-Stage Drug Fluorosulfonylation.

Aryl sulfonyl fluorides are prominently featured in organic synthesis and medicinal chemistry. Herein, a metal-free photoredox-catalyzed three-component assembly of aryl sulfonyl fluoride via aryl sulfonyl ammonium salt intermediate has been reported. A variety of structurally diverse aryl sulfonyl fluorides were synthesized rapidly from dibenzothiophenium (DBT) salts under mild conditions by using KHF2 as the fluorine source. Notably, this methodology can be employed as an efficient and sustainable approach for late-stage drug fluorosulfonylation. Good yields and broad functionality tolerance were the features of this methodology. Moreover, the derivatization of aryl sulfonyl fluoride molecules was also demonstrated to showcase its synthetic utility.