Coumarins as Potential Inhibitors of DNA Polymerases and Reverse Transcriptases. Searching New Antiretroviral and Antitumoral Drugs

Abstract

Human Immunodeficiency Virus (HIV) is the viral agent of Acquired Immunodeficiency Syndrome (AIDS), and at present, there is no effective vaccine against HIV. Reverse Transcriptase (RT) is an essential enzyme for retroviral replication, such as HIV as well as for other RNA infectious viruses like Human T lymphocyte virus. Polymerases act in DNA metabolism, modulating different processes like mitosis, damage repair, transcription and replication. It has been widely documented that DNA Polymerases and Reverse Transcriptases serve as molecular targets for antiviral and antitumoral chemotherapy. Coumarins are oxygen heterocycles that are widely distributed throughout the plant kingdom. Natural coumarins have attraction due to their bioactive properties such as tumor promotion inhibitory effects, and anti-HIV activity. Coumarins and derivates exhibit potent inhibitory effects on HIV-1 replication in lymphocytes and compounds isolated from Calophyllum inophyllum or DCK derivates showed inhibitory activity against human RT. Furthermore, natural isocoumarins isolated from cultures of fungi or hydroxycoumarins were able to inhibit human DNA polymerase. In view of their importance as drugs and biologically active natural products, and their medicinally useful properties, extensive studies have been carried out on the synthesis of coumarin compounds in recent years. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), a class of antiretroviral chemotherapeutic agents, act by binding to an allosteric pocket showing, generally, low toxicity. This work tries to summarize the investigation about natural and synthetic coumarins with the ability to inhibit key enzymes that play a crucial role in DNA metabolism and their possible application as antiretroviral and antitumoral agents.

Antiviral Natural Products against Hepatitis-A Virus

“…Coumarin and its derivatives have been used to manufacture drugs serving as anticoagulants including warfarin, acenocoumarin and phenprocoumon, and also for production of novobiocin, a potent inhibitor of bacterial DNA gyrase [63]. Coumarins (2H-chromen-2-ones) are recognized as a privileged bioactive scaffold for designing new agents with high affinity and specificity to various molecular targets [64], especially as antiviral agents [65]. In recent years, 4-Phenylcoumarins (neoflavones) which are bio-isosteres of flavonoids, have been of much interest as lead target structure for the discovery of new antiviral agents [66,67].…”

Synthesis and Antiretroviral Activity of 6-Acetyl-coumarin Derivatives against HIV-1 Infection

“…Various reports showed the antiretroviral potency of coumarins via inhibition of retroviral enzymes i.e. reverse transcriptase, protease and integrase [16][17][18][19][20] . Due to wide range of biological activity, synthesis of coumarins in laboratory has now become the prime interest of medicinal chemists.…”

Coumarin: A Natural, Privileged and Versatile Scaffold for Bioactive Compounds

“…This review is focused on the design, synthesis, bio-pharmacological evaluation, and data analysis of a large number of coumarin derivatives, mainly developed in our group, as monoamine oxidase (MAO), cholinesterase (ChE), and aromatase (AR) inhibitors, and as multitarget agents addressing neurodegenerative diseases (NDs). Coumarin derivatives studied by other groups will be also taken into account, to expand the analysis of the structure–activity relationships (SARs), but not in an extensive/comprehensive way, most of them being already quoted in a recent book [ 1 ] and exhaustive reviews [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ].…”