Activating endogenous resolution pathways by soluble epoxide hydrolase inhibitors for the management of COVID-19.

Anti-inflammatory, specialized proresolving mediators such as resolvins, protectins, maresins, and lipoxins derived from polyunsaturated acids may play a potential role in lung diseases as they protect different organs in animal disease models. Polyunsaturated fatty acids are an important resource for epoxy fatty acids (EET, EEQ, and EDP) that mediate a broad array of anti-inflammatory and proresolving mechanisms, such as mitigation of the cytokine storm. However, epoxy fatty acids are rapidly metabolized by soluble epoxide hydrolase (sEH). In animal studies, administration of sEH inhibitors (sEHIs) increases epoxy fatty acid levels, reduces lung inflammation, and improves lung function, making it a viable COVID-19 treatment approach. Thus, using sEHIs to activate endogenous resolution pathways might be a novel method to minimize organ damage in severe cases and improve outcomes in COVID-19 patients. This review focuses on the use of sEH inhibitors to activate endogenous resolution mechanisms for the treatment of COVID-19.

The recent outbreaks of human coronaviruses: A medicinal chemistry perspective.

Coronaviruses (CoVs) infect both humans and animals. In humans, CoVs can cause respiratory, kidney, heart, brain, and intestinal infections that can range from mild to lethal. Since the start of the 21st century, three ß-coronaviruses have crossed the species barrier to infect humans: severe-acute respiratory syndrome (SARS)-CoV-1, Middle East respiratory syndrome (MERS)-CoV, and SARS-CoV-2 (2019-nCoV). These viruses are dangerous and can easily be transmitted from human to human. Therefore, the development of anticoronaviral therapies is urgently needed. However, to date, no approved vaccines or drugs against CoV infections are available. In this review, we focus on the medicinal chemistry efforts toward the development of antiviral agents against SARS-CoV-1, MERS-CoV, SARS-CoV-2, targeting biochemical events important for viral replication and its life cycle. These targets include the spike glycoprotein and its host-receptors for viral entry, proteases that are essential for cleaving polyproteins to produce functional proteins, and RNA-dependent RNA polymerase for viral RNA replication.

Chloroquine Analogs: An Overview of Natural and Synthetic Quinolines as Broad Spectrum Antiviral Agents.

SARS-CoV-2, a positive single-stranded RNA enveloped coronavirus, currently poses a global health threat. Drugs with quinoline scaffolds have been studied to repurpose their useful broad-spectrum properties into treating various diseases, including viruses. Preliminary studies on the quinoline medications, chloroquine and hydroxychloroquine, against SARS-CoV-2, have shown to be a potential area of interest for drug development due to their ability to prevent viral entry, act as anti-inflammatory modulators, and inhibit key enzymes allowing reduced viral infectivity. In addition to Chloroquine and Hydroxychloroquine, we discussed analogs of the drugs to understand the quinoline scaffold's potential antiviral mechanisms. The heterocyclic scaffold of quinoline can be modified in many ways, primarily through the modification of its substituents. We studied these different synthetic derivatives to understand properties that could enhance its antiviral specificity thoroughly. Chloroquine and its analogs can act on various stages of the viral life cycle, pre and post entry. In this study, we reviewed chloroquine and its synthetic and natural analogs for their antiviral properties in a variety of viruses. Furthermore, we reviewed the compound's potential abilities to attenuate symptoms associated with viral infections. Natural compounds that share scaffolding to chloroquine can act as antivirals or attenuate symptoms through the stimulation of the host immune system or reduction of oxidative stress. Furthermore, we discuss perspectives of the drug's repurposing due to its ability to inhibit the beta-hematin formation and to be a Zinc Ionophore.

Design, synthesis and anticancer activity of 2-amidomethoxy-1,4-naphthoquinones and its conjugates with Biotin/polyamine.

In continuation with the previous work, a series of 5-hydroxy-2-amidomethoxy-1,4-naphthoquinones were prepared to establish the structure-activity relationship studies toward anticancer activity (IC50 in µM) against three cell lines; colo205 (colon adenocarcinoma), T47D (breast ductal carcinoma) and K562 (chronic myelogenous leukemia). Among the synthesized compounds, naphthoquinone amines, 5 (0.8; 0.6; 0.8), 14 (0.8; 0.6; 0.5) and the amine precursor, 4 (1.3; 0.3; 1.0) displayed potent anticancer activities. A tumor targeting drug delivery system was achieved by synthesizing the conjugate 6 (1.4; 0.5; 1.1) of naphthoquinone-amine 5 and Biotin which also proved its potency. Finally, to introduce polyamine conjugate, spermidine was attached with 2-amidomethoxy-1,4-naphthoquinone. The naphthoquinone-spermidine conjugate 27 (1.2; 1.7; 1.7) also retained the activity. Thus, potent naphthoquinone amines were explored and Biotin/polyamine conjugate was developed as tumor targeting drug delivery system.

Identification of diphenylalkylisoxazol-5-amine scaffold as novel activator of cardiac myosin.

To identify novel potent cardiac myosin activator, a series of diphenylalkylisoxazol-5-amine compounds 4-7 have been synthesized and evaluated for cardiac myosin ATPase activation. Among the 37 compounds, 4a (CMA at 10 µM = 81.6%), 4w (CMA at 10 µM = 71.2%) and 6b (CMA at 10 µM = 67.4%) showed potent cardiac myosin activation at a single concentration of 10 µM. These results suggested that the introduction of the amino-isoxazole ring as a bioisostere for urea group is acceptable for the cardiac myosin activation. Additional structure-activity relationship (SAR) studies were conducted. Para substitution (-Cl, -OCH3, -SO2N(CH3)2) to the phenyl rings or replacement of a phenyl ring with a heterocycle (pyridine, piperidine and tetrahydropyran) appeared to attenuate cardiac myosin activation at 10 µM. Additional hydrogen bonding acceptor next to the amino group of the isoxazoles did not enhance the activity. The potent isoxazole compounds showed selectivity for cardiac myosin activation over skeletal and smooth muscle myosin, and therefore these potent and selective isoxazole compounds could be considered as a new series of cardiac myosin ATPase activators for the treatment of systolic heart failure.

A medicinal chemistry perspective of drug repositioning: Recent advances and challenges in drug discovery.

Drug repurposing is a strategy consisting of finding new indications for already known marketed drugs used in various clinical settings or highly characterized compounds despite they can be failed drugs. Recently, it emerges as an alternative approach for the rapid identification and development of new pharmaceuticals for various rare and complex diseases for which lack the effective drug treatments. The success rate of drugs repurposing approach accounts for approximately 30% of new FDA approved drugs and vaccines in recent years. This review focuses on the status of drugs repurposing approach for various diseases including skin diseases, infective, inflammatory, cancer, and neurodegenerative diseases. Efforts have been made to provide structural features and mode of actions of drugs.

Recent discovery and development of inhibitors targeting coronaviruses.

Human coronaviruses (CoVs) are enveloped viruses with a positive-sense single-stranded RNA genome. Currently, six human CoVs have been reported including human coronavirus 229E (HCoV-229E), OC43 (HCoV-OC43), NL63 (HCoV-NL63), HKU1 (HCoV-HKU1), severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), and MiddleEast respiratory syndrome (MERS) coronavirus (MERS-CoV). They cause moderate to severe respiratory and intestinal infections in humans. In this review, we focus on recent advances in the research and development of small-molecule anti-human coronavirus therapies targeting different stages of the CoV life cycle.

Exploration of imidazole and imidazopyridine dimers as anticancer agents: Design, synthesis, and structure-activity relationship study.

Dimerization of proteins/receptors plays a critical role in various cellular processes, including cell proliferation and differentiation. Therefore, targeting such dimeric proteins/receptors by dimeric small molecules could be a potential therapeutic approach to treating various diseases, including inflammation-associated diseases like cancer. A novel series of bis-imidazoles (13-18) and bis-imidazo[1,2-a]pyridines (19-28) were designed and synthesized from Schiff base dimers (1-12) for their anticancer activities. All the synthesized compounds were screened for anticancer activities against three cancer cell lines, including cervical (HeLa), breast (MDA-MB-231), and renal cancer (ACHN). From structure-activity relationship studies, imidazo[1,2-a]pyridines (19-28) showed remarkable cytotoxic activities, with compounds 19 and 24 showing the best inhibitory activities against all three cell lines. Especially, both 19 and 24 were very effective against the breast cancer cell line (19, GI50 = 0.43 µM; 24, GI50 = 0.3 µM), exceeding the activity of the control adriamycin (GI50 = 0.51 µM). The in vivo anticancer activity results of compounds 19 and 24 were comparable with those of the animals treated with the standard drug tamoxifen. Therefore, the dimeric imidazo[1,2-a]pyridine scaffold could serve as a potential lead for the development of novel anticancer agents.

Design and synthesis of sulfonamidophenylethylamides as novel cardiac myosin activator.

The sulfonamidophenylethylamide analogues were explored for finding novel and potent cardiac myosin activators. Among them, N-(4-(N,N-dimethylsulfamoyl)phenethyl-N-methyl-5-phenylpentanamide (13, CMA at 10 µM = 48.5%; FS = 26.21%; EF = 15.28%) and its isomer, 4-(4-(N,N-dimethylsulfamoyl)phenyl-N-methyl-N-(3-phenylpropyl)butanamide (27, CMA at 10 µM = 55.0%; FS = 24.69%; EF = 14.08%) proved to be efficient cardiac myosin activators both in in vitro and in vivo studies. Compounds 13 (88.2 + 3.1% at 5 µM) and 27 (46.5 + 2.8% at 5 µM) showed positive inotropic effect in isolated rat ventricular myocytes. The potent compounds 13 and 27 were highly selective for cardiac myosin over skeletal and smooth muscle myosin, and therefore these potent and selective amide derivatives could be considered a new class of cardiac myosin activators for the treatment of systolic heart failure.

Exploration of diphenylalkyloxadiazoles as novel cardiac myosin activator.

To explore novel cardiac myosin activator, a series of diphenylalkyl substituted 1,3,4-oxadiazoles and 1,2,4-oxadiazoles have been prepared and tested for cardiac myosin ATPase activation in vitro. In all cases, three carbon spacer between the oxadiazole core and one of the phenyl ring was considered crucial. In case of 1,3,4-oxadiazole, zero to two carbon spacer between oxadiazole core and other phenyl ring are favorable. Phenyl ring can be replaced by cyclohexyl moiety. In case of 1,2,4-oxadiazole, zero or one carbon spacer between the oxadiazole and other phenyl ring are favorable. Introduction of hydrogen bonding donor (NH) group at the 2nd position of the 1,3,4-oxadiazole enhances the activity. Substitutions on either of the phenyl rings or change of phenyl ring to other heterocycle are not tolerated for both the oxadiazoles. The prepared oxadiazoles showed selective activation for cardiac muscle over smooth and skeleton muscles.

Investigation of chemical reactivity of 2-alkoxy-1,4-naphthoquinones and their anticancer activity.

To establish the structure-activity relationship of 5-hydroxy-1,4-naphthoquinones toward anticancer activity, a series of its derivatives were prepared and tested for the activity (IC50 in µM) against three cell lines; colo205 (colon adenocarcinoma), T47D (breast ductal carcinoma) and K562 (chronic myelogenous leukemia). Among them 2 (IC50: 2.3; 2.0; 1.4 µM), 6 (IC50: 1.9; 2.2; 1.3 µM), 9 (IC50: 0.7; 1.7; 0.9 µM) and 10 (IC50:1.7; 1.0; 1.2 µM) showed moderate to excellent activity. Our perception toward the DNA substitution of alkoxy groups at the C2 position of these naphthoquinones for the anticancer activity led us to investigate their reactivity of substitution toward dimethylamine as a nucleophile. The ease of the substitution of alkoxy groups at the C2 position with dimethylamine is strongly accelerated by hydroxyl group at C5 position and is well correlated with the found anticancer activity results.

Inhibitors of Melanogenesis: An Updated Review.

Melanins are pigment molecules that determine the skin, eye, and hair color of the human subject to its amount, quality, and distribution. Melanocytes synthesize melanin and provide epidermal protection from various stimuli, such as harmful ultraviolet radiation, through the complex process called melanogenesis. However, serious dermatological problems occur when there is excessive production of melanin in different parts of the human body. These include freckles, melasma, senile lentigo, pigmented acne scars, and cancer. Therefore, controlling the production of melanin is an important approach for the treatment of pigmentation related disorderes. In this Perspective, we focus on the inhibitors of melanogenesis that directly/indirectly target a key enzyme tyrosinase as well as its associated signaling pathways.

Design and synthesis of sulfonamidophenylethylureas as novel cardiac myosin activator.

To optimize the lead urea scaffold 1 and 2 as selective cardiac myosin ATPase activator, a series of urea derivatives have been synthesized to explore its structure activity relationship. Among them N,N-dimethyl-4-(2-(3-(3-phenylpropyl)ureido)ethyl)benzenesulfonamide (13, CMA = 91.6%, FS = 17.62%; EF = 11.55%), N,N-dimethyl-4-(2-(1-methyl-3-(3-phenylpropyl)ureido)ethyl)benzene sulfonamide (40, CMA = 52.3%, FS = 38.96%; EF = 24.19%) and N,N-dimethyl-4-(2-(3-methyl-3-(3-phenylpropyl)ureido)ethyl)benzenesulfonamide (41, CMA = 47.6%, FS = 23.19%; EF = 15.47%) proved to be efficient to activate the cardiac myosin in vitro and in vivo. Further the % change in ventricular cell contractility at 5 µM of 13 (47.9 ± 3.2), 40 (45.5 ± 2.4) and 41 (63.5 ± 2.2) showed positive inotropic effect in isolated rat ventricular myocytes. The potent compounds 13, 40, 41 were highly selective for cardiac myosin over skeletal and smooth muscle myosin, thus proving them these new urea derivatives is a novel scaffold for discovery of cardiac myosin activators for the treatment of systolic heart failure.

Recent development of signaling pathways inhibitors of melanogenesis.

Human skin, eye and hair color rely on the production of melanin, depending on its quantity, quality, and distribution, Melanin plays a monumental role in protecting the skin against the harmful effect of ultraviolet radiation and oxidative stress from various environmental pollutants. However, an excessive production of melanin causes serious dermatological problems such as freckles, solar lentigo (age spots), melasma, as well as cancer. Hence, the regulation of melanin production is important for controlling the hyper-pigmentation. Melanogenesis, a biosynthetic pathway to produce melanin pigment in melanocyte, involves a series of intricate enzymatic and chemical catalyzed reactions. Several extrinsic factors include ultraviolet radiation and chemical drugs, and intrinsic factors include molecules secreted by surrounding keratinocytes or melanocytes, and fibroblasts, all of which regulate melanogenesis. This article reviews recent advances in the development of melanogenesis inhibitors that directly/indirectly target melanogenesis-related signaling pathways. Efforts have been made to provide a description of the mechanism of action of inhibitors on various melanogenesis signaling pathways.

Discovery of novel 3-(hydroxyalkoxy)-2-alkylchromen-4-one analogs as interleukin-5 inhibitors.

A series of novel chromen-4-one analogs 9a-d and 10a-u was designed, synthesized and evaluated for their IL-5 inhibitory activity. Most of the chromen-4-one analogs showed strong inhibitory activity in low micro molar potency. Among them, 5-(cyclohexylmethoxy)-3-(3-hydroxypropoxy)-2-isopropyl-4H-chromen-4-one (10t, 90.0% inhibition at 30 µM, IC50 = 5.5 µM, CLogP = 4.76887) and 2-cyclohexyl-5-(cyclohexylmethoxy)-3-(3-hydroxypropoxy)-4H-chromen-4-one (10u, 95.5% inhibition at 30 µM, IC50 = 3.0 µM, CLogP = 5.96187) showed the best inhibition. The structure activity relationship reveals that the hydrophobic cyclohexylmethoxy group at the position 5 of the chromen-4-one ring A is preferable than at position 6 and the dual hydrogen bonding acceptor property on the chromen-4-one ring should be important for the inhibitory activity. In addition, the optimum length of the side chain at position 3 of chromen-4-one ring is critical for the donation of hydrogen to the binding site and the 3-hydroxypropoxy group showed the best activity. Moreover, the conformational restrictor (isopropyl, cyclohexyl group) at position 2 is much more favorable for the formation of effective conformer of side chain with hydrogen bonding donor property of these chromen-4-one analogs.

Exploration of flexible phenylpropylurea scaffold as novel cardiac myosin activators for the treatment of systolic heart failure.

A series of flexible urea derivatives have been synthesized and demonstrated as selective cardiac myosin ATPase activator. Among them 1-phenethyl-3-(3-phenylpropyl)urea (1, cardiac myosin ATPase activation at 10 µM = 51.1%; FS = 18.90; EF = 12.15) and 1-benzyl-3-(3-phenylpropyl)urea (9, cardiac myosin ATPase activation = 53.3%; FS = 30.04; EF = 18.27) showed significant activity in vitro and in vivo. The change of phenyl ring with tetrahydropyran-4-yl moiety viz., 1-(3-phenylpropyl)-3-((tetrahydro-2H-pyran-4-yl)methyl)urea (14, cardiac myosin ATPase activation = 81.4%; FS = 20.50; EF = 13.10), and morpholine moiety viz., 1-(2-morpholinoethyl)-3-(3-phenylpropyl)urea (21, cardiac myosin ATPase activation = 44.0%; FS = 24.79; EF = 15.65), proved to be efficient to activate the cardiac myosin. The potent compounds 1, 9, 14 and 21 were found to be selective for cardiac myosin over skeletal and smooth myosins. Thus, these urea derivatives are potent scaffold to develop as a newer cardiac myosin activator for the treatment of systolic heart failure.

Exploration of SAR for novel 2-benzylbenzimidazole analogs as inhibitor of transcription factor NF-κB.

A novel series of 2-benzylbenzimidazole analogs was designed, synthesized and investigated for their in vitro activities against LPS induced NF-κB inhibition in RAW 264.7 cells using the SEAP assay. Among them, 4-((4-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)phenol (6e, >100% inhibition at 30 µM, IC50 = 3.0 µM), 4-((5-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)phenol (6j, 96% inhibition at 30 µM, IC50 = 4.0 µM) and 2-((4-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)phenol (6k, 95% inhibition at 30 µM, IC50 = 5.0 µM) showed strong inhibitory activity. The structure activity relationship confirmed that the substitution on benzimidazole ring A with hydrophobic cyclohexylmethoxy group at position 4 or 5 markedly enhances the activity. In addition, the hydrophilic hydrogen bonding donor group (OH) at position 2 or 4 on phenyl ring B connected with one methylene spacer to the benzimidazole ring is favorable for the inhibitory activity. However, hydrophobic (-OCH3 and -Cl) groups on phenyl ring B decrease the activity.

Skin whitening agents: medicinal chemistry perspective of tyrosinase inhibitors.

Melanogenesis is a process to synthesize melanin, which is a primary responsible for the pigmentation of human skin, eye and hair. Although numerous enzymatic catalyzed and chemical reactions are involved in melanogenesis process, the enzymes such as tyrosinase and tyrosinase-related protein-1 (TRP-1) and TRP-2 played a major role in melanin synthesis. Specifically, tyrosinase is a key enzyme, which catalyzes a rate-limiting step of the melanin synthesis, and the downregulation of tyrosinase is the most prominent approach for the development of melanogenesis inhibitors. Therefore, numerous inhibitors that target tyrosinase have been developed in recent years. The review focuses on the recent discovery of tyrosinase inhibitors that are directly involved in the inhibition of tyrosinase catalytic activity and functionality from all sources, including laboratory synthetic methods, natural products, virtual screening and structure-based molecular docking studies.

Downregulation of melanogenesis: drug discovery and therapeutic options.

Melanin, primarily responsible in humans for hair, eye and skin pigmentation, is produced by melanocytes through a process called melanogenesis. However, the abnormal accumulation of melanin causes dermatological problems such as café-au-lait macules ephelides (freckles), solar lentigo (age spots) and melasma, as well as cancer and vitiligo. Hence the regulation of melanogenesis is very important for treating hyperpigmentary disorders. Numerous antimelanogenic agents that target tyrosinase activity and/or stability, melanosome maturation, transfer and trafficking, or melanogenesis-related signaling pathways have been developed. This article reviews recent advances in research and development of human tyrosinase and melanogenesis-related signaling pathway inhibitors. Attempts have been made to provide a complete description of the mechanism of action of inhibitors on various melanogenesis signaling pathways.

Macrocyclic Hepatitis C Virus NS3/4A Protease Inhibitors: An Overview of Medicinal Chemistry.

Hepatitis C virus (HCV) is a causative agent of hepatitis C infectious disease that primarily affects the liver, ranging in severity from a mild illness lasting a few weeks to a lifelong illness. The 9.6 kb RNA genome of HCV encodes approximately 3000 amino acid polyprotein that must be processed by host and viral proteases into both structural (S) and non-structural (NS) proteins, respectively. Targeting the serine protease NS3 with an activating factor NS4A, i.e., NS3/4A has been considered as one of the most attractive targets for the development of anti-HCV therapy. Although there is no vaccine available, antiviral medicines cure approximately 90% of the persons with hepatitis C infection. On the other hand, efficacy of these medications can be hampered due to the rapid drug and cross resistances. To date, all developed HCV NS3/4A inhibitors are mainly peptide-based compounds derived from the cleavage products of substrate. Specifically macrocyclic peptidomimetics have rapidly emerged as a classical NS3/4A protease inhibitors for treating the HCV infection. This review highlights the development of macrocyclic anti-HCV NS3/4A protease, as well as clinically important inhibitors developed from linear peptides, discovered during the last 12 years (2003-2015) from all sources, including laboratory synthetic methods, virtual screening and structure-based molecular docking studies. We emphasize the rationale behind the design, study of structure-activity relationships, and mechanism of inhibitions and cellular effect of the macrocyclic inhibitors.