P2Y12 is a platelet surface protein which is responsible for the amplification of P2Y1 response. It plays a crucial role in platelet aggregation and thrombus formation through an ADP-induced platelet activation mechanism. Despite that P2Y12 platelets' receptor is an excellent target for developing antiplatelet agents, only five approved medications are currently in clinical use which are classified into thienopyridines and nucleoside-nucleotide derivatives. In the past years, many attempts for developing new candidates as P2Y12 inhibitors have been made. This review highlights the importance and the role of P2Y12 receptor as part of the coagulation cascade, its reported congenital defects, and the type of assays which are used to verify and measure its activity. Furthermore, an overview is given of the clinically approved medications, the potential naturally isolated inhibitors, and the synthesised candidates which were tested either in-vitro, in-vivo and/or clinically. Finally, we outline the in-silico attempts which were carried out using virtual screening, molecular docking and dynamics simulations in efforts of designing novel P2Y12 antagonists. Various phytochemical classes might be considered as a corner stone for the discovery of novel P2Y12 inhibitors, whereas a wide range of ring systems can be deliberated as leading scaffolds in that area synthetically and theoretically.
The C-3, C-17 and C-22 congeners of pentacyclic triterpenoids reduced lantadene A (3), B (4) and 22β-hydroxyoleanolic acid (5) were synthesized and were tested in vitro for their NF-κB and IKKβ inhibitory potencies and cytotoxicity against A549 lung cancer cells. The lead congeners 12 and 13 showed IC50 of 0.56 and 0.42 μmol, respectively against TNF-α induced activation of NF-κB. The congeners 12 and 13 exhibited inhibition of IKKβ in a single-digit micromolar dose and at the same time, 12 and 13 showed marked cytotoxicity against A549 lung cancer cells with IC50 of 0.12 and 0.08 μmol, respectively. The lead ester congeners were stable in the acidic pH, while hydrolyzed readily in the human blood plasma to release the active parent moieties.
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.
Copper (II) complexes synthesized from the products of condensation of S-methyl- and S-benzyldithiocarbazate with 2,5-hexanedione (SMHDH2 and SBHDH2 respectively) have been characterized using various physicochemical (elemental analysis, molar conductivity, magnetic susceptibility) and spectroscopic (infrared, electronic) methods. The structures of SMHDH2, its copper (II) complex, CuSMHD, and the related CuSBHD complex as well as a pyrrole byproduct, SBPY, have been determined by single crystal X-ray diffraction. In order to provide more insight into the behaviour of the complexes in solution, electron paramagnetic resonance (EPR) and electrochemical experiments were performed. Antibacterial activity and cytotoxicity were evaluated. The compounds, dissolved in 0.5% and 5% DMSO, showed a wide range of antibacterial activity against 10 strains of Gram-positive and Gram-negative bacteria. Investigations of the effects of efflux pumps and membrane penetration on antibacterial activity are reported herein. Antiproliferation activity was observed to be enhanced by complexation with copper. Preliminary screening showed Cu complexes are strongly active against human breast adenocarcinoma cancer cell lines MDA-MB-231 and MCF-7.
N-methyl-d-aspartate receptors (NMDAR) are critically involved in the pathogenesis of Alzheimer's disease (AD). Acting as an open-channel blocker, the anti-AD drug memantine preferentially targets NMDAR overactivation, which has been proposed to trigger neurotoxic events mediated by amyloid β peptide (Aβ) and oxidative stress. In this study, we applied a multifunctional approach by conjugating memantine to ferulic acid, which is known to protect the brain from Aβ neurotoxicity and neuronal death caused by ROS. The most interesting compound (7) behaved, like memantine, as a voltage-dependent antagonist of NMDAR (IC50 = 6.9 μM). In addition, at 10 μM concentration, 7 exerted antioxidant properties both directly and indirectly through the activation of the Nrf-2 pathway in SH-SY5Y cells. At the same concentration, differently from the parent compounds memantine and ferulic acid alone, it was able to modulate Aβ production, as revealed by the observed increase of the non-amyloidogenic sAPPα in H4-SW cells. These findings suggest that compound 7 may represent a promising tool for investigating NMDAR-mediated neurotoxic events involving Aβ burden and oxidative damage.
The family Sterculiaceae is one of the most important families among flowering plants. Many of its members demonstrate medicinal properties and have been used for the treatment of various ailments and wounds. A wide range of compounds including alkaloids, phenyl propanoids, flavonoids, terpenoids and other types of compounds including hydrocarbons, sugars, quinones, phenolic acids, lactones, lignans, amine and amides have been isolated from several species in this family. Few studies have reported that some extracts and single compounds isolated from this family exhibited several biological activities, such as antimicrobial, anti-inflammatory, antioxidant and cytotoxic activities. The present review is an effort to provide information about the traditional uses, phytochemistry and pharmacology of species from family Sterculiaceae, and to uncover the gaps and potentials requiring further research opportunities regarding the chemistry and pharmacy of this family.
Curcumin is a small organic molecule with pleiotropic biological activities. However, its multiple structural-pharmacokinetic challenges prevent its development into a clinical drug. Various structural modifications have been made to improve its drug profile. In this review, we focus on the methods adopted in the synthesis of asymmetric curcumin derivatives and their biological activities and forecast the future of this exciting class of compounds in the field of medicine.
Acarbose, miglitol, and voglibose are the inhibitors of α-glucosidase enzyme and being clinically used for the management of type-II diabetes mellitus. However, many adverse effects are also associated with them. So, the development of new therapeutic agents is an utmost interest in medicinal chemistry research. Current study is based on the identification of new α-glucosidase inhibitors. For that purpose, hydrazinyl arylthiazole based pyridine derivatives 1-39 were synthesized via two step reaction and fully characterized by spectroscopic techniques EI-MS, HREI-MS, (1)H-, and (13)C NMR. However, stereochemistry of the iminic bond was confirmed by NOESY. All compounds were subjected to in vitro α-glucosidase inhibitory activity and found many folds active (IC50 = 1.40 ± 0.01-236.10 ± 2.20 μM) as compared to the standard acarbose having IC50 value of 856.45 ± 5.60 μM. A limited structure-activity relationship was carried out in order to make a presumption about the substituent's effect on inhibitory activity which predicted that substituents of more negative inductive effect played important role in the activity as compared to the substituents of less negative inductive effect. However, in order to have a good understanding of ligand enzyme interactions, molecular docking study was also conducted. In silico study was confirmed that substituents like halogens (Cl) and nitro (NO2) which have negative inductive effect were found to make important interactions with active site residues.
The current mechanistic study was conducted to explore the effects of increased lipophilicity of binuclear silver(I)-NHC complexes on cytotoxicity. Two new silver(I)-N-Heterocyclic Carbene (NHC) complexes (3 and 4), having lypophilic terminal alkyl chains (Octyl and Decyl), were derived from meta-xylyl linked bis-benzimidazolium salts (1 and 2). Each of the synthesized compounds was characterized by microanalysis and spectroscopic techniques. The complexes were tested for their cytotoxicity against a panel of human cancer c as well normal cell lines using MTT assay. Based on MTT assay results, complex 4 was found to be selectively toxic towards human colorectal carcinoma cell line (HCT 116). Complex 4 was further studied in detail to explore the mechanism of cell death and findings of the study revealed that complex 4 has promising pro-apoptotic and anti-metastatic activities against HCT 116 cells. Furthermore, it showed pronounced cytostatic effects in HCT 116 multicellular spheroid model. Hence, binuclear silver(I)-NHC complexes with longer terminal aliphatic chains have worth to be further studied against human colon cancer for the purpose of drug development.
Early detection and efficient treatment of cancer disease remains a drastic challenge in 21st century. Throughout the bulk of funds, studies, and current therapeutics, cancer seems to aggressively advance with drug resistance strains and recurrence rates. Nevertheless, nanotechnologies have indeed given hope to be the next generation for oncology applications. According to US National cancer institute, it is anticipated to revolutionize the perspectives of cancer diagnosis and therapy. With such success, nano-hybrid strategy creates a marvelous preference. Herein, graphene-gold based composites are being increasingly studied in the field of oncology, for their outstanding performance as robust vehicle of therapeutic agents, built-in optical diagnostic features, and functionality as theranostic system. Additional modes of treatments are also applicable including photothermal, photodynamic, as well as combined therapy. This review aims to demonstrate the various cancer-related applications of graphene-gold based hybrids in terms of detection and therapy, highlighting the major attributes that led to designate such system as a promising ally in the war against cancer.
Malaria has been teasing human populations from a long time. Presently, several classes of antimalarial drugs are available in market, but the issues of toxicity, lower efficacy and the resistance by malarial parasites have decreased their overall therapeutic indices. Thus, the search for new promising antimalarials continues, however, the battle against malaria is far from over. Ferroquine is a derivative of chloroquine with antimalarial properties. It is the most successful of the chloroquine derivatives. Not only ferroquine, but also its derivatives have shown promising potential as antimalarials of clinical interest. Presently, much research is dedicated to the development of ferroquine derivatives as safe alternatives to antimalarial chemotherapy. The present article describes the structural, chemical and biological features of ferroquine. Several classes of ferroquine derivatives including hydroxyferroquines, trioxaferroquines, chloroquine-bridged ferrocenophanes, thiosemicarbazone derivatives, ferrocene dual conjugates, 4-N-substituted derivatives, and others have been discussed. Besides, the mechanism of action of ferroquine has been discussed. A careful observation has been made into pharmacologically significant ferroquine derivatives with better or equal therapeutic effects to that of chloroquine and ferroquine. A brief discussion of the toxicities of ferroquine derivatives has been made. Finally, efforts have been made to discuss the current challenges and future perspectives of ferroquine-based antimalarial drug development.
Amongst heterocyclic compounds, quinoline and its derivatives are advantaged scaffolds that appear as a significant assembly motif for developing new drug entities. Aminoquinoline moiety has gained significant attention among researchers in the 21stcentury. Considering the biological and pharmaceutical importance of aminoquinoline derivatives, herein, we review the recent developments (since 2019) in various biological activities of the 4-aminoquinoline scaffold hybridized with diverse heterocyclic moieties such as quinoline, pyridine, pyrimidine, triazine, dioxine, piperazine, pyrazoline, piperidine, imidazole, indole, oxadiazole, carbazole, dioxole, thiazole, benzothiazole, pyrazole, phthalimide, adamantane, benzochromene, and pyridinone. Moreover, by gaining knowledge about SARs, structural insights, and molecular targets, this review may help medicinal chemists design cost-effective, selective, safe, and more potent 4-aminoquinoline hybrids for diverse biological activities.
HIV infection is a major challenge to mankind and a definitive cure or a viable vaccine for HIV is still elusive. HIV-1 is constantly evolving and developing resistant against clinically used anti-HIV drugs thus posing serious hurdles in the treatment of HIV infection. This prompts the need to developed new anti-HIV drugs; preferentially adopting intelligent ways to counteract an evolving virus. Highly Active Anti-Retroviral Therapy (HAART): a strategy involving multiple targeting through various drugs has proven beneficial in the management of AIDS. However, it is a complex regimen with high drug load, increased risk of drug interactions and adverse effects, which lead to poor patient compliance. Reverse transcriptase (RT) and Integrase (IN) are two pivotal enzymes in HIV-1 lifecycle with high structural and functional analogy to be perceived as drug-able targets for novel dual-purpose inhibitors. Designed multi-functional ligand (DML) is a modern strategy by which multiple targets can be exploited using a single chemical entity. A single chemical entity acting on multiple targets can be much more effective than a complex multi-drug regimen. The development of such multifunctional ligands is highly valued in anti-HIV drug discovery with the proposed advantage of being able to stop two or more stages of viral replication cycle. This review will encompass the evolution of the RT-IN dual inhibitory scaffolds reported so far and the contribution made by the leading research groups over the years in this field.
A significant advancement in the field of epigenetic drug discovery has been evidenced in recent years. Epigenetic alterations are hereditary, nevertheless reversible variations to DNA or histone adaptations that regulate gene function individualistically of the fundamental sequence. The design and synthesis of various drugs targeting epigenetic regulators open a new door for epigenetic-targeted therapies to parade worthwhile therapeutic potential for haematological and solid malignancies. Several ongoing clinical trials on dual targeting strategy are being conducted comprising HDAC inhibitory component and an epigenetic regulating agent. In this perspective, the review discusses the pharmacological aspects of HDAC and other epigenetic regulating factors as dual inhibitors as an emerging alternative approach for combination therapies.
Peroxisome Proliferator-Activated Receptor γ (PPARγ) activators have drawn great recent attention in the clinical management of type 2 diabetes mellitus, prompting several attempts to discover and optimize new PPARγ activators. With this in mind, we explored the pharmacophoric space of PPARγ using seven diverse sets of activators. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of accessing self-consistent and predictive quantitative structure-activity relationship (QSAR) (r2(71)=0.80, F=270.3, r2LOO=0.73, r2PRESS against 17 external test inhibitors=0.67). Three orthogonal pharmacophores emerged in the QSAR equation and were validated by receiver operating characteristic (ROC) curves analysis. The models were then used to screen the national cancer institute (NCI) list of compounds. The highest-ranking hits were tested in vitro. The most potent hits illustrated EC50 values of 15 and 224 nM.
In our drug discovery program, a series of 2-thioxo-pyrazolo[1,5-a][1,3,5]triazin-4-ones were designed, synthesized and evaluated for their TP inhibitory potential. All the synthesized analogues conferred a varying degree of TP inhibitory activity, comparable or better than positive control, 7-deazaxanthine (7-DX, 2) (IC50 value = 42.63 μM). A systematic approach to the lead optimization identified compounds 3c and 4a as the most promising TP inhibitors, exhibiting mixed mode of enzyme inhibition. Moreover, selected compounds demonstrated the ability to attenuate the expression of the angiogenic markers (viz. MMP-9 and VEGF) in MDA-MB-231 cells at sublethal concentrations. In addition, molecular docking studies revealed the plausible binding orientation of these inhibitors towards TP, which was in accordance with the experimental results. Taken as a whole, these compounds would constitute a new direction for the design of novel TP inhibitors with promising antiangiogenic properties.
A novel and potent series of ene-amides featuring azetidines has been developed as FabI inhibitors active against drug resistant Gram-positive pathogens particularly staphylococcal organisms. Most of the compounds from the series possessed excellent biochemical inhibition of Staphylococcus aureus FabI enzyme and whole cell activity against clinically relevant MRSA, MSSA and MRSE organisms which are responsible for significant morbidity and mortality in community as well as hospital settings. The binding mode of one of the leads, AEA16, in Escherichia coli FabI enzyme was determined unambiguously using X-ray crystallography. The lead compounds displayed good metabolic stability in mice liver microsomes and pharmacokinetic profile in mice. The in vivo efficacy of lead AEA16 has been demonstrated in a lethal murine systemic infection model.
Unpleasant side effects and resistance development remained the Achilles heel of chemotherapy. Since low tumor-selectivity and monotonous effect of chemotherapy are closely related to such bottleneck, targeting tumor-selective multi-functional anticancer agents may be an ideal strategy in the search of new safer drugs. Herein, we report the discovery of compound 21, a nitro-substituted 1,5-diphenyl-3-styryl-1H-pyrazole that possesses dual functional characteristics. The 2D- and 3D-culture-based studies revealed that 21 not only could induce ROS-independent apoptotic and EGFR/AKT/mTOR-mediated autophagic cell deaths in EJ28 cells simultaneously but also has the ability in inducing cell death at both proliferating and quiescent zones of EJ28 spheroids. The molecular modelling analysis showed that 21 possesses EGFR targeting capability as it forms stable interactions in the EGFR active site. Together with its good safety profile in the zebrafish-based model, the present study showed that 21 is promising and may lead to the discovery of tumor-selective multi-functional anti-cancer agents.
Transforming growth factor-β (TGF-β) is a member of a superfamily of pleiotropic proteins that regulate multiple cellular processes such as growth, development and differentiation. Following binding to type I and II TGF-β serine/threonine kinase receptors, TGF-β activates downstream signaling cascades involving both SMAD-dependent and -independent pathways. Aberrant TGF-β signaling is associated with a variety of diseases, such as fibrosis, cardiovascular disease and cancer. Hence, the TGF-β signaling pathway is recognized as a potential drug target. Various organic molecules have been designed and developed as TGF-β signaling pathway inhibitors and they function by either down-regulating the expression of TGF-β or by inhibiting the kinase activities of the TGF-β receptors. In this review, we discuss the current status of research regarding organic molecules as TGF-β inhibitors, focusing on the biological functions and the binding poses of compounds that are in the market or in the clinical or pre-clinical phases of development.
Herein we report the design, synthesis and biological evaluation of structurally modified ciprofloxacin, norfloxacin and moxifloxacin standard drugs, featuring amide functional groups at C-3 of the fluoroquinolone scaffold. In vitro antimicrobial testing against various Gram-positive bacteria, Gram-negative bacteria and fungi revealed potential antibacterial and antifungal activity. Hybrid compounds 9 (MIC 0.2668 ± 0.0001 mM), 10 (MIC 0.1358 ± 00025 mM) and 13 (MIC 0.0898 ± 0.0014 mM) had potential antimicrobial activity against a fluoroquinolone-resistant Escherichia coli clinical isolate, compared to ciprofloxacin (MIC 0.5098 ± 0.0024 mM) and norfloxacin (MIC 0.2937 ± 0.0021 mM) standard drugs. Interestingly, compound 10 also exerted potential antifungal activity against Candida albicans (MIC 0.0056 ± 0.0014 mM) and Penicillium chrysogenum (MIC 0.0453 ± 0.0156 mM). Novel derivatives and standard fluoroquinolone drugs exhibited near-identical cytotoxicity levels against L6 muscle cell-line, when measured using the MTT assay.