Manoj Manickam

Skin whitening agents: medicinal chemistry perspective of tyrosinase inhibitors

Abstract 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.

Inhibitors of melanogenesis: a patent review (2009 -- 2014)

Introduction: Melanogenesis is the process of producing the melanin pigment, in which a series of chemical and enzymatic pathways are involved. Modulation at any level of this process would become an important approach in the treatment of hyper- or hypopigmentation-related diseases. Since hyperpigmentation covers important issue in cosmetics, there is a need of such review to understand and update this field to the public domain. Areas covered: In this review, authors discuss most recent melanogenesis inhibitors published in the patents since 2009. The up-to-date overview of classical catechol-based tyrosinase inhibitors to non-classical melanogenesis inhibitors with different mechanism of action is discussed. Inhibitors including small-interfering RNA and peptides from ∼ 30 patents and their associated literature are also discussed. Expert opinion: Although a huge number of melanogenesis inhibitors have been reported, the future studies should be focused towards the identification of new inhibitors with a clear mechanism. The next breakthrough in the field therefore, is likely to come from the detailed structure–activity relationship studies of thioureas with improved therapeutic profiles. Targeting other parameters such as number or size of melanosomes, maturation of melanosomes and expression of melanogenic enzymes may give the best results to overcome toxicity and other formulation problems.

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.

Synthesis and SAR studies of bis-chromenone derivatives for anti-proliferative activity against human cancer cells.

A novel family of 3-((4-oxo-4H-chromen-3-yl)methyl)-4H-chromen-4-one (bis-chromone) derivatives were designed, synthesized and studied for their anti-cancer activity using the XTT assay for the growth inhibition against various human cancer cells. Among them, 3-((5-(cyclohexylmethoxy)-4-oxo-4H-chromen-3-yl)methyl)-7-methoxy-4H-chromen-4-one and 3-((5-(cyclohexylmethoxy)-4-oxo-4H-chromen-3-yl)methyl)-7-hydroxy-4H-chromen-4-one showed micromolar level of in vitro anti-proliferative activity against human cancer cell lines. The SAR studies indicated bis-chromone as a basic scaffold to design anticancer agents. The 5-cyclohexylmethoxy on the first chromenone ring and electron donating group such as CH3, OCH3 or hydrogen bonding group (OH) on the other chromenone ring of bis-chromone increased the activity. However, saturation of one of chromenone to chromanone in bis-chromones decreased the activity.

An Overview of Severe Acute Respiratory Syndrome–Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy

Severe acute respiratory syndrome (SARS) is caused by a newly emerged coronavirus that infected more than 8000 individuals and resulted in more than 800 (10–15%) fatalities in 2003. The causative agent of SARS has been identified as a novel human coronavirus (SARS-CoV), and its viral protease, SARS-CoV 3CLpro, has been shown to be essential for replication and has hence been recognized as a potent drug target for SARS infection. Currently, there is no effective treatment for this epidemic despite the intensive research that has been undertaken since 2003 (over 3500 publications). This perspective focuses on the status of various efficacious anti-SARS-CoV 3CLpro chemotherapies discovered during the last 12 years (2003–2015) from all sources, including laboratory synthetic methods, natural products, and virtual screening. We describe here mainly peptidomimetic and small molecule inhibitors of SARS-CoV 3CLpro. Attempts have been made to provide a complete description of the structural features and binding modes of these inhibitors under many conditions.

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.

Exploration of 2-benzylbenzimidazole scaffold as novel inhibitor of NF-κB

For finding the novel inhibitor of nuclear factor κB activity, a series of benzimidazole derivatives were rationally designed, synthesized and systematically studied for their in vitro activities against LPS induced NF-κB inhibition in RAW 264.7 cells using the SEAP assay based on the flexible chalcone JSH ((E)-1-(2-hydroxy-6-(isopentyloxy)phenyl)-3-(4-hydroxy phenyl)prop-2-en-1-one) which was previously reported. Although most of the benzimidazole derivatives showed strong inhibitory activity in low micromolar potency, 2-(4-methoxybenzyl)-1H-benzo[d]imidazole (3m; IC50=1.7 μM) and 2-(2-methoxybenzyl)-1H-benzo[d]imidazole (3n; IC50=2.4 μM) showed the best inhibition. The structure activity relationship revealed that 2-benzylbenzimidazole scaffold with hydrogen bonding acceptor on phenyl ring appears as a pharmacophore.

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.

Middle East Respiratory Syndrome-Coronavirus (MERS-CoV): An UpdatedOverview and Pharmacotherapeutics

In 2012, a novel human coronavirus (CoV) associated with severe respiratory tract infection, Middle East Respiratory Syndrome (MERS-CoV) was first recognized and since then 1401 patients were infected across the world (26 countries) with this virus, 543 (~39%) of which died. The diseases present severe respiratory infection often with shock, acute kidney injury and coagulopathy. Its human-to-human transmission through close contact has raised a global concern about its potential pandemic. This review describes the strategies used to develop effective pharmacotherapeutics for MERS-CoV, which are based on the experience gained from SARS-CoV outbreak in 2003.

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.