Recent Developments In Drug Discovery Research Articles

Molecular Insights into Coumarin Analogues as Antimicrobial Agents: Recent Developments in Drug Discovery

Simple SummaryCoumarins are a large family of benzopyrones, and more than 1300 coumarins have been reported to date. Natural, as well as synthetic, coumarins have demonstrated a diverse activity spectrum. On the other hand, the demands of the current health scenario witnessing morbidity and mortality due to microbial infections and multidrug-resistant bacterial strains, the well-reported phytochemical coumarin can be of interest. Some of the well-reported coumarin analogues as antimicrobial agents include β-lactum derivatives, coumarin-based 1,2,3-triazole compounds, the miconazole analogue, coumarin-substituted pyrazole hybrids, pyranocoumarin, coumarin−sulphonamide hybrids, pyranocoumarins, coumarin−sulphonamide derivatives, chromenylpyrazoles candidates, 3-amidocoumarins analogues, uracil−coumarin hybrids, indolinedione−coumarin hybrids, coumarin−imidazole hybrids, coumarin-fused pyrazolones and methyl thiazole derivatives, coumarin−theophylline hybrids, etc. In the present review, several methods for the synthesis of coumarin derivatives as antimicrobial agents are reported, along with structure−activity relationship (SAR) studies focusing on the developments reported since 2016. A major global health risk has been witnessed with the development of drug-resistant bacteria and multidrug-resistant pathogens linked to significant mortality. Coumarins are heterocyclic compounds belonging to the benzophenone class enriched in different plants. Coumarins and their derivatives have a wide range of biological activity, including antibacterial, anticoagulant, antioxidant, anti-inflammatory, antiviral, antitumour, and enzyme inhibitory effects. In the past few years, attempts have been reported towards the optimization, synthesis, and evaluation of novel coumarin analogues as antimicrobial agents. Several coumarin-based antibiotic hybrids have been developed, and the majority of them were reported to exhibit potential antibacterial effects. In the present work, studies reported from 2016 to 2020 about antimicrobial coumarin analogues are the focus. The diverse biological spectrum of coumarins can be attributed to their free radical scavenging abilities. In addition to various synthetic strategies developed, some of the structural features include a heterocyclic ring with electron-withdrawing/donating groups conjugated with the coumarin nucleus. The suggested structure−activity relationship (SAR) can provide insight into how coumarin hybrids can be rationally improved against multidrug-resistant bacteria. The present work demonstrates molecular insights for coumarin derivatives having antimicrobial properties from the recent past. The detailed SAR outcomes will benefit towards leading optimization during the discovery and development of novel antimicrobial therapeutics.

Therapeutic Outcomes of Isatin and Its Derivatives against Multiple Diseases: Recent Developments in Drug Discovery.

Isatin (1H indole 2, 3-dione) is a heterocyclic, endogenous lead molecule recognized in humans and different plants. The isatin nucleus and its derivatives are owed the attention of researchers due to their diverse pharmacological activities such as anticancer, anti-TB, antifungal, antimicrobial, antioxidant, anti-inflammatory, anticonvulsant, anti-HIV, and so on. Many research chemists take advantage of the gentle structure of isatins, such as NH at position 1 and carbonyl functions at positions 2 and 3, for designing biologically active analogues via different approaches. Literature surveys based on reported preclinical, clinical, and patented details confirm the multitarget profile of isatin analogues and thus their importance in the field of medicinal chemistry as a potent chemotherapeutic agent. This review represents the recent development of isatin analogues possessing potential pharmacological action in the years 2016–2020. The structure–activity relationship is also discussed to provide a pharmacophoric pattern that may contribute in the future to the design and synthesis of potent and less toxic therapeutics.

A review on Hydroxamic Acids: Widespectrum Chemotherapeutic Agents

Recent developments in drug discovery have highlighted the ability of hydroxamic acids to form complexes with various metal ions, in particular iron, zinc, magnesium and calcium, and this imparts them with a number of unique biological and pharmacological properties. This review provides information on the most significant developments of the hydroxamate compounds in the medicinal area with a focus on Suberoylanilide hydroxamic acid (SAHA) and its derivatives with antibacterial, antifungal, antiviral, antimalarial, antitubercular and anticancer effect and their possible molecular mechanisms. One of the latest favorable developments has been on developing SAHA and its hybrids as potent anti-tuberculosis drugs. Moreover, the combination of the hydroxamic acids with other pharmacophore groups in one molecule can lead to the creation of a huge number of new compounds with promising properties as a multifunctional drug. Also, within the last decade, active research has focused to create these compounds into a class of new antiviral drugs designed to treat influenza, hepatitis C, and other viral infections. Thus, both linear hydroxamic acids and cyclic acids having the uniqueness of the set of bioactive properties, have been compiled here and could be looked forward as the basis for the development of effective drugs and forpilot scale productions through nitrile and amides via chemical and biological transformations using amidase and acyltransferase enzymes. Such synthesis of medicinally significant compounds from amide containing waste derived feedstocks using microbial agents is also a key factor for stimulating bioeconomy.

ATP-Diphosphohydrolases in Parasites: Localization, Functions and Recent Developments in Drug Discovery.

ATP-diphosphohydrolases (EC 3.6.1.5), also known as ATPDases, NTPases, NTPDases, EATPases or apyrases, are enzymes that hydrolyze a variety of nucleoside tri- and diphosphates to their respective nucleosides, being their activities dependent on the presence of divalent cations, such as calcium and magnesium. Recently, ATP-diphosphohydrolases were identified on the surface of several parasites, such as Trypanosoma sp, Leishmania sp and Schistosoma sp. In parasites, the activity of ATPdiphosphohydrolases has been associated with the purine recuperation and/or as a protective mechanism against the host organism under conditions that involve ATP or ADP, such as immune responses and platelet activation. These proteins have been suggested as possible targets for the development of new antiparasitic drugs. In this review, we will comprehensively address the main aspects of the location and function of ATP-diphosphohydrolase in parasites. Also, we performed a detailed research in scientific database of recent developments in new natural and synthetic inhibitors of the ATPdiphosphohydrolases in parasites.

Ecto-nucleotidase inhibitors: recent developments in drug discovery.

Ecto-nucleotidases are nucleotide metabolizing enzymes that are divided into four different families; nucleoside triphosphate diphosphohydrolases (NTPDases), ecto-5'-nucleotidase (ecto-5'-NT), nucleotide pyrophosphatase/phosphodiesterases (NPPs), and alkaline phosphatases (APs). These enzymes are responsible for the hydrolysis of nucleotidases (nucleoside 5'-triphosphates, 5'-diphosphates and 5'-monophosphates). Ecto-nucleotidases modulate P1- and P2-receptor-mediated signaling. Alterations in extracellular nucleotide and adenosine level can increase or decrease P1 and P2 activity. Potent and selective ligands for certain ectonucleotidase are important as pharmacological tools to investigate the (patho)physiological roles of these enzymes. Furthermore, such ligands are required to study their potential as novel drugs, e.g., as immunomodulatory agents, for the treatment of cancer, cardiovascular or central nervous system disorders. Hence, this review aims to provide an overview of ecto-nucleotidases inhibitors developed so far.

Recent developments in drug discovery for leishmaniasis and human African trypanosomiasis.

Leishmaniasis is a parasitic disease that presents four main clinical syndromes: cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL), visceral leishmaniasis/kala azar (VL), and post kala azar dermal leishmaniasis (PKDL). Causative Leishmania are protozoan parasites that are transmitted among mammalian hosts by phlebotomine sandflies. In mammalian hosts, parasite cells proliferate inside the host phagocytic cells as round amastigotes. Infection of sandflies with Leishmania occurs during insect feeding on infected mammalian hosts. After introduction into the insect gut together with the blood meal, Leishmania amastigotes transform into elongated flagellated promastigotes that propagate in the insect gut. A new round of infection is initiated after the infected sandfly takes a blood meal from a naive mammalian host and introduces Leishmania parasites into the bite wound in the host dermis (Scheme 1). More than 20 different Leishmania species have been found to cause human leishmaniasis (Table 1). Leishmaniasis is endemic in 98 countries and is closely associated with poverty. More than a million new cases are reported per year and 350 million people are at risk of contracting the infection. For the most severe form of leishmaniasis, VL, ∼300 000 new cases are estimated to occur annually resulting in ∼40 000 deaths. Approximately 90% of all VL cases occur in 3 endemic foci: 1. India, Bangladesh, and Nepal; 2. East Africa; and 3. Brazil. In spite of the high prevalence, currently available treatments for leishmaniasis are inadequate. Pentavalent antimonials, the standard treatment for leishmaniasis for many decades, are not efficacious in Bihar (∼60% of VL cases worldwide) any longer due to widespread resistance to the drug in this region. Several new VL treatments have emerged during the past 10–15 years, but each has serious shortcomings (summarized in Table 2). These include paromomycin (injectable, long treatment, region-dependent efficacy), miltefosine (cost, teratogenicity, long treatment), and liposomal amphotericin B (cost, hospitalization, region-dependent efficacy). An additional challenge is represented by patients with HIV/VL coinfections who are more difficult to cure (lower initial and final cure rates), have greater susceptibility to drug toxicity, and have higher rates of death and relapse. Due to the limitations of the existing treatments, better drugs are urgently needed. Ideally, new VL drugs would be efficacious across all endemic regions, would affect cure in ≤10 days, and would cost <$10 per course (for a complete target product profile for new VL drugs, which was formulated by DNDi, see Table 4).1 Here we describe the disease history and parasite biology followed by a summary of the currently available treatments and, finally, review reports of novel small molecules with antileishmanial activity.

Hydroxamate, a Key Pharmacophore Exhibiting a Wide Range of Biological Activities

Naturally occurring hydroxamic acid derivatives are biosynthesized by microorganisms (siderophores) and plants (benzoxazinoids). Recent developments in drug discovery have highlighted the numerous biological and pharmacological properties that the hydroxamic acid function may possess, leading to therapeutic applications. These properties may be explained by its ability to chelate metals via the presence of two oxygen atoms. Their pharmacological activities can be divided into three groups. The first concerns the ability of these hydroxamic acid derivatives to scavenge metals (particularly iron), which leads to antioxidant, antimicrobial and metal detoxification activities. The latter is largely used to treat iron overload in patients. The second group of activities is related to their ability to inhibit metallo-enzymes, which gives them a wide range of pharmacological effects: antimicrobial, anti-inflammatory and antitumor. The third group is linked to the capacity of these compounds to generate nitric oxide, which confers hypotensive activity. However, hydroxamates exhibit relatively low stability in vivo, which can be overcome by the synthesis of appropriately designed analogs. For this purpose, many different strategies have been proposed. In this review, we compare and discuss the various synthetic pathways used to obtain the most complex of them, the N-substituted hydroxamic acids. We conclude that among numerous protocols reported so far, the direct N-substitution of hydroxamic acids, the acylation of the appropriate N-O derivative and the direct oxidation of the corresponding amide allow for the synthesis of a wide range of new biologically active compounds.

The role of triple therapy with protease inhibitors in hepatitis C virus genotype 1 naïve patients

With the introduction of direct-acting oral antiviral agents we are on the verge of a new era that will transform the treatment landscape. This review discusses recent developments in drug discovery for hepatitis C protease inhibitors. First generation protease inhibitors will offer higher sustained viral response rates in naïve populations when combined with standard pegylated interferon and ribavirin. However, these dramatic gains will be partially offset by new challenges in viral resistance and increased adverse events.

New therapies in the management of hepatitis C virus

The present review discusses recent developments in drug discovery for hepatitis C. We are on the verge of a new era with the introduction of direct acting oral agents that will transform the treatment landscape. Both healthcare providers and patients need to stay abreast of these changes that will influence decisions to treat. This article will discuss the most promising up-to-date hepatitis C virus antiviral therapies in clinical investigation as well as the associated clinical trial results. First generation protease inhibitors will offer higher sustained viral response rates for both naive (70-80%) and treatment-experienced (40-50%) populations when added to standard pegylated interferon and ribavirin. However, these dramatic gains will be partially offset by new challenges with viral resistance and increased adverse events. There are currently a number of drugs under investigation that target the enzymes involved in hepatitis C virus replication. Year 2011 should bring the approval of the first generation of protease inhibitors that will offer higher cure rates for genotype 1 patients and open the door for the eventual testing of interferon-free regimens.

The Nuclear Receptor Superfamily and Drug Discovery

Targeting the nuclear receptors: The ligand-binding domain of the glucocorticoid receptor (ribbon) bound with the ligand, dexamethasone (space-filling) is just one of the many pictures that are becoming clearer in the field of nuclear receptor (NR) research. Recent developments in drug discovery show great promise for the treatment of many NR-related diseases.

Pharmacological Evaluation of Cannabinoid Receptor Ligands in a Mouse Model of Anxiety: Further Evidence for an Anxiolytic Role for Endogenous Cannabinoid Signaling

Extracts of Cannabis sativa have been used for their calming and sedative effects for centuries. Recent developments in drug discovery have suggested that modulation of neuronal endogenous cannabinoid signaling systems could represent a novel approach to the treatment of anxiety-related disorders while minimizing the adverse effects of direct acting cannabinoid receptor agonists. In this study, we evaluated the effects of direct cannabinoid receptor agonists and antagonists and endocannabinoid-modulating drugs on anxiety-like behavior in mice using the elevated-plus maze. We found that the direct CB1 receptor agonists (1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol (CP 55,940) (0.001-0.3 mg/kg) and 2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo [1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate) (WIN 55212-2) (0.3-10 mg/kg) increased time spent on the open arms (To) at low doses only. At the highest doses tested, both compounds altered overall locomotor activity. In contrast, Delta9-tetrahydrocannabinol (0.25-10 mg/kg) produced a dose-dependent reduction in To. The endocannabinoid uptake/catabolism inhibitor 4-hydroxyphenylarachidonylamide (AM404) (0.3-10 mg/kg) produced an increase in To at low doses and had no effect at the highest dose tested. The fatty acid amide hydrolase inhibitor cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB597) (0.03-0.3 mg/kg) produced a monophasic, dose-dependent increase in To. The CB1 receptor antagonists N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716) (1-10 mg/kg) and N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) (1-10 mg/kg) produced dose-related decreases in To. These data indicate that activation of CB1 cannabinoid receptors reduces anxiety-like behaviors in mice and further support an anxiolytic role for endogenous cannabinoid signaling. These results suggest that pharmacological modulation of this system could represent a new approach to the treatment of anxiety-related psychiatric disorders.