A Brief Review: Biological Implications of Naphthoquinone Derivatives

 

Bigyan R. Jali*, R. Behura, Soumya. R. Barik, S. Parveen, Spandan. P. Mohanty, R. Das

Department of Chemistry, Veer Surendra Sai University of Technology Burla Sambalpur, Odisha, 768018

 

ABSTRACT:

Naphthoquinone derivatives are a class of organic compounds that interact with many biological systems. Now it is found that the use of naphthoquinone derivatives against cancer cells, microbes and different kinds of disorder in the human body. Extensive researches on diverse effect of naphthoquinone derivatives have been going on since long specifically in the field of pharmaceuticals. Herein; we wish to report the naphthoquinone derivatives having biological activities such as antifungal, antibacterial, anticancer, antiparasitic, anti-oxidant properties.

 

The naphthoquinone derivatives (1-2) showed excellent anti-cancer activity.

 

 

 

1.      INTRODUCTION:

Naphthoquinone derivatives play vital role in pharmaceutical industry and they show the potent biological activities.^1-5 During the last decade, incredible growth in recognition of biological activities of naphthoquinone derivatives has vast interest due to their potential activity.^6-10 Naphthoquinone derivatives are of specific attention due to their presence as natural products and as environmental chemicals¹¹. Thus, naphthoquinone derivatives occupy a unique place in pharmaceutical industry because of their wide application in biological activities such as antifungal, antimicrobial, anti-inflammatory, antioxidant, antiviral, anti-tubercular, anticancer, and antagonistic^12-14. Many of the synthesized naphthoquinone derivatives containing commercial drugs are now readily available in the market; while some are in clinical trials. This review shows on the biological activities of naphthoquinone derivatives.

 

2. Biological activities of Naphthoquinone and its derivative:

2.1: Antifungal and antiparasitic activities:

Naphthoquinone derivatives showed potent antifungal and antimicrobial activity. It is well known that naphthoquinone derivatives have significant antifungal and antimicrobial activities. Naphthoquinone derivatives¹⁵ showed antifungal activity against various strains of pathogenic fungi; it revealed that these derivatives exhibited potent antifungal activity and it found that these derivatives were useful for clinical applications on inflammatory agents with antifungal activity¹⁶. The systemic fungal infection reasons of mortality in HIV infections and the emergence of multi resistance strains. It is very improved to discover new antifungal compounds. Candida is mostly accountable for the primarily infections sourced by fungi and candida albicans the vital species in fungal infections¹⁷. Now a days; it is found that the non-albicans species is also used selectively for antifungal drugs. The compound (1) revealed dominant antifungal activity¹⁸ against candida albicans with MIC of 0.2 μgml^-1; and the compound,¹⁹ 2,3-dichloro-5,6,7,8-tetrahydro-5,5-dimethylanthracene-1,4-dione (2) exhibited a better antifungal activity against candida albicans. However; the compounds 3 and 4 introverted c. krusei with MIC₉₀  =2 to 2.4 μg/ml, respectively. The derivative 5 showed the better activity against trychophyton mentagrophytes with MIC₉₀ 1.3μgml^-1.^20-21 However; compound 6 showed the most active against trychophyton rubrum with MIC₉₀ of 5.0 μgml^-1. The compounds 7, 8 and 9 were examined as for in vitro antifungal²² activity against candida albicans and candida tropicalis, aspergillus-niger, fusarumoxysporum and trichophytontonsurans. It exhibited compounds 7-9 (Scheme-1) very prone against candida tropicalis, aspergillus-niger, fusarumoxysporum and trichophytontonsurans with the minimum inhibitory concentration MIC₅₀ of 0.2 μgml^-1. The author attributes the presence of the N-atom permits the geometric modification and of their reduction intermediates. On the other hand; Mannich base derivatives were examined as for in vitro antifungal activity by the broth micro-dilution method reported by Greco and his co-workers.²³ It was surprising that derivatives 10-12 were very prone against candida albicans. The author suggested that the derivatives 10-12 demonstrated excellent fungistatic and fungicidal activity against candida albicans with MIC of 40-67 μgml^-1and led to development of drug resistance. The author attributes the presence of phenyl moiety helps in increasing the fungistatic and fungicidal activity against candida albicans. It indicates that these derivatives are significant role for clinical use; since the complete elimination of the pathogen is the safest option. Compound 13 exhibited²⁴ better activity against candida albicans and cryptococcus neoformans and also potent activity than clinically prevalent antifungal drug Fluconazole against s. schenckii with MIC₅₀ of 1.56 μgml^-1.

 

From last few decades, the incredible growths of naphthoquinone derivative inhibit the growth of parasites are well documented.^25-30 In this context; Glaxo and co-workers reported the 1,4-naphthoquinone derivative namely, (2-[trans4-(4'-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone is used for malaria treatment³¹. According to World Health Organization (WHO), 39 million people were infected in schistosomiasis caused by s. mansoni parasite. Amino naphthoquinone derivatives exhibited potent activity against b. glabrata, with IC₅₀=3.2 μgml^-1. Apart from that the compounds (14-17) exhibited better activity.³² Toxoplasmosis is caused by toxoplasma gondiiis parasite. It is responsible for infection in human foetuses at the stage of pregnancy. The naphthoquinone derivative such as 6-(4-methylpentyl)-2-pyrrolidine-1,4-naphthoquinone exhibited in vitro against toxoplasma gondii with IC₅₀ of 0.32 μM. The compound showed better activity than other deivatives.³³

 

2.2. Anti-inflammatory and anti-oxidant activities:

Naphthoquinone and its derivatives showed potent anti-inflammatory and anti-oxidant activity. Anti-inflammatory of naphthoquinone derivatives was studied extensively by Kuo³⁴ and his research groups. They found compounds 18-21 (Scheme-2) exhibited better anti-inflammatory activity.^35-36 Compounds 22-24 also showed remarkable anti-inflammatory activity.^37-38Antioxidant activity of naphthoquinone deivative³⁹ was examined using DPPH radical-scavenging assay. The derivatives 25-27 showed better antioxidant activity. Apart from that the compound (25) showed most potent antioxidant activities due to the presence of furan rings. The author attributes the presence of O-atom interacts with the double bonds of-the ring and it causes the relocation of the electrons. Derivative 18 illustrated the excellent antioxidant capacity due to its dimeric nature.^40-41 The antioxidant activities⁴²of the compounds 28 and 29 was investigated using superoxide radical scavenging using nitro blue tetrazolium chloride assay. The scavenging activities of the tested derivatives were measured at a dose level of 1000 μgml^-1and by using ascorbic acid as standard antioxidant activity. It found that the presence of electron attracting groups such as -OH groups attached to naphthoquinone moiety exhibited stronger antioxidant activity as compared to ascorbic acid. As a result, compounds 28 and 29 exhibited more antioxidant activity than ascorbic acid.

 

2.3. Anti-bacterial and anti-viral activities:

Naphthoquinone derivatives exhibited better antibacterial activities higher than various reference drugs.⁴³A series of naphthoquinone derivatives were synthesized and examined against M. tuberculosis. The naphthoquinone derivative (36) showed better activity than reported reference drugs with IC₅₀ of 1.87 µM. The author attributes due to the presence of chlorine and fluorine group on aniline moiety enhance the anti-mycobacterial activity.⁴⁴ The naphthoquinone derivatives (37) showed better antibacterial activity with MIC of 2.1 μgml^-1against bacillus subtil. From the molecular docking study, it revealed that 1,4-naphthoquinone derivatives are 8 times more active than other naphthoquinone derivatives on the gram positive bacteria.^45-47a

 

2.4. Anti-tuberculosis and anti-convulsant activities:

Tuberculosis is a chronic infectious disease, one of the major enemies of the humanity. It is interesting to design high biological naphthoquinone derivatives with extremely low-toxic substances superior to the available drugs in their activity and efficiency. Naphthoquinone moieties showed potent anti-tuberculosis activity. It revealed that the compound 30 exhibited better inhibitory activity with MIC of 25 μgml^-1 and IC₅₀ value of 7.6 μgml^-1.⁴⁸ It is found that the mannich base derivatives were examined for in vitro anti-tuberculosis activity against mycobacterium tuberculosis. It revealed that the naphthoquinone derivatives (38) showed better anti-tuberculosis behaviour. Amide derivatives of 4-amino-1,2-naphthoquinone showed anticonvulsant activity. The compounds 31 and 32 (Scheme-3) were active at the dose 10 mg/kg and these derivatives showed better anticonvulsant effect. These derivatives showed anticonvulsant effect comparable to phenytoin. It exhibits for development of new anticonvulsant drug development⁴⁹.

 

 

 

Scheme 1: Naphthoquinone derivatives showing antifungal and antiparasitic activities.

 

 

Scheme 2: Naphthoquinone derivatives showing anti-inflammatory and anti-oxidant activities.

 

2.5. Anticancer activities:

From the last decades, it is well known that naphthoquinone derivatives were extensively used for anti cancer drugs. Naphthoquinone unit produce the reactive oxygen species, which plays the vital role in DNA damage and it leads to cell death⁵⁰. Due to their unique electron accepting properties, naphthoquinone and its derivatives showed the excellent cytotoxic activity. Due to this, cytotoxic of these derivatives are mainly depends on their size and geometry.^51-52 In this contexts_, Kusumaningrum and co-workers reported a series of naphthoquinone derivatives and evaluated their anticancer activity against human cancer cell lines such as HepG2, HuCCA-1, A549 and MOLT-3 and normal embryonic lung cells (MRC-5). It revealed that the compounds 33 and 34 showed excellent behaviour against all cancer cell lines with IC₅₀ values of 4.758, 2.364 and 12.279 mM than other derivatives. The author found that the presences of phenyl amino substituents lead to improved cytotoxic activity⁵³. Wu et.al^54a reported a series of naphthoquinone derivat ives and examined there in vitro anticancer activity against human cancer cell lines. The cytotoxicity of these derivatives was assayed against HT-29, SW480, HepG2, MCF-7 and HL-60 cells by the MTT assay. It revealed that compound 35 showed a better cytotoxicity. The compound 35 also showed better cytotoxicity against human colorectal adenocarcinoma HT-29 cells with IC₅₀=1.99±0.04 μM.

 

 

Scheme 3: Naphthoquinone derivatives showing anti-tuberculosis, anticonvulsant and anticancer activities.

 

3. CONCLUSIONS:

These review showed recent medicinal chemistry investigations for naphthoquinone derivatives of promising biological activities. All derivatives show the excellent biological activities such as anti-tuberculosis, anticonvulsant, anticancer, antifungal, antibacterial, antiviral, anti-inflammatory and anticonvulsant properties. These activities were the results of the actions of naphthoquinone derivatives on biological systems by the interaction of the pharmacophoric and by the lipophilic character allowing the penetration through the biological membranes. The activities were examined by using various biological systems such as cell lines, bacteria, viruses, mice and monolayer and bilayer membranes. It will be interesting to prepare new analogues of the most active derivatives having either heterocyclic rings or open chains which may be nontoxic and with significant HIV and anticancer activity.

 

4. ACKNOWLEDGEMENTS:

The authors thank Department of Chemistry, Veer Surendra Sai University of Technology Burla, Sambalpur, Odisha.

 

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Accepted on 12.05.2018        © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(8): 3698-3702.