Pandemic conditions did not slow us down rather shook us to speed up the drug development projects:
At Istanbul Medipol University, International School of Medicine Faculty Member, and part of the Research Institute for Health Sciences and Technologies (SABITA), Center of Drug Discovery and Development Assoc. Prof. Mustafa GÜZEL’s team produced drugs that will reduce the foreign dependency in the treatment of Covid-19. His team took part in two different ways Covid-19 drug development projects among 18 projects within the TUBİTAK Covid-19 Vaccine and Drug Development Platform. Dr. Guzel is the project manager in which the team synthesized three Covid-19 drugs with completely domestic infrastructure and force. The other project is a natural product study, the effectiveness of some natural products which were investigated against Covid-19.
As the world shaken by pandemic Covid-19, small molecule inhibitors have previously been heavily investigated in different studies as possible therapeutics in the treatment of SARS-CoV-2. In Turkey we began investigating potential treatment options and decided to collaborate with a local pharma company named Atabay. Within a short period of time, we have successfully completed full lab and industrial scale of three molecules that have been vastly used for Covid-19 treatment such as Favipiravir (Fav), Hydroxychloroquine (HCQ), and Remdesivir (Rem). The coronavirus disease-2019 (Covid-19) outbreak all over the world has led the researchers to strive to develop drugs or vaccines to prevent or halt the progression of this culprit. As the literature supports, Favipiravir is approved by some countries, including India, for Covid-19 treatment. Favipiravir has shown rapid viral clearance and faster clinical improvement. Various treatment recommendations include Favipiravir for Covid-19 treatment we began to investigate and immediately started synthetic strategy for these medicines. During our study we have established cost effective route to expedite the process and filed a domestic patent and currently submitted manuscript for publication. (ACS Journal: Organic Process Research and Development).
Turkey’s domestic and national medicine was produced by synthesizing the raw material of the drug called Favipiravir, which was used in the treatment of Covid-19 and was seen to reduce the recovery period of the disease from 11 days to 4 days in a clinical study conducted in China. In the project supported by TUBİTAK, the local synthesis of the drug named “Favipiravir”, developed by the team led by Assoc. Prof. Mustafa Guzel, was licensed by the Ministry of Health, and made available to patients. This drug, marketed as “FavicovirTM”, was first produced on a laboratory scale. Afterwards, industrial scale studies were completed, and production was carried out. As a result of the rapid completion of the bio-equivalence studies of the drug, the license of the drug was obtained on 10 July 2020.
The synthesis pathway of favipiravir, consisting of 8 steps, was carried out with a team led by Assoc. Prof. Mustafa Guzel from Istanbul Medipol University and with the coordination of Zeynep Atabay Taskent from Atabay Pharmaceuticals and Fine Chemicals. Favipiravir has been synthesized entirely with domestic and national means from domestic raw materials to products and has become available for use in the treatment of patients under the name of “FAVICOVIR”. Eight-step total synthesis of favipiravir drug active ingredient was performed. In the first stage, 3-aminopyrazine-2-carboxylic acid was converted to methyl ester (2) by Fischer esterification. The pyrazine ring is then brominated at the 6-position (3). The 3-amino group was converted to 3-hydroxy group by diazotization and diazonium salt hydrolysis (4). Its methyl ester in the 2-position was converted to the carboxamide group by aminolysis (5). The critical intermediate (6) was obtained by treating this intermediate with POCl3. (Figure 1).
Director of the Pharmaceutical Discovery and Development Center Dr. Guzel, stated that they prevented the import of drugs by producing the domestic synthesis of the drug called “Favipiravir” used in the treatment of Covid-19, “With this study, we have supported our country with millions of dollars. We developed a patent-pending molecule for Covid-19. Since the Ministry of Health included the drug ‘Favipiravir’ in its standard treatment protocol, we also localized that drug. Thus, the product was developed domestically without being imported. We provided millions of dollars of support to our country. We have succeeded in producing this drug, which has a high price, at a much lower cost. Especially the domestic drug development industry needs to accelerate. This improves our self-confidence. Saying ‘We can develop our molecules and produce our raw materials’ inspires our self-esteem. “The fate of this virus is still unpredictable. We are trying to do our best to support our country in this regard.” said.
Figure 1: Synthesis of intermediate 3,6-dichloropyrazine-2-carbonitrile (6)
Favipiravir active ingredient, one of the 3 drugs within the scope of the project, was first developed in Japan by Toyama Chemicals, affiliated with Fujifilm, and started to be used in the treatment of influenza under the name Avigan. Later, the production license was transferred to a Chinese company, and after 2019, with the expiration of the patent protection period, it was possible for other companies to produce. When Covid-19 started to be seen in our country in March 2020 and considered as the pandemic, Favipiravir was imported from China and used in the treatment of Covid-19 patients with moderate or severe pneumonia. During the pandemic process, many countries have closed their customs gates and prioritized their own needs. There were difficulties in obtaining many products, including medicines. For this reason, it was an important success to produce Favipiravir with domestic and national means and deliver it to the public. As our Favipiravir Synthesis workforce, our post-doctoral researchers Dr. Hacer Karatas, Dr. Essam Hanashalshahaby, our undergraduate student at the school of pharmacy Y. Enes Butun and the pharmaceutical production manager Unal Catal from Atabay Pharmaceuticals & Fine Chemicals, made an intense selfless work in a very short time. We synthesized Favipiravir in this way. These efforts will strengthen our country in the fight against the pandemic, as well as contributing to our health sector to provide better quality service to our people in this difficult process we are going through. It will also contribute to our national economy by reducing foreign dependency.
As of the beginning of August 2021 the infected population reached 203+ million with the death toll rising more than 4.3 million. Numerous efforts in natural product drug development are reported for the treatment of Coronavirus. For this reason, research on herbal medicines that can be domestic/national drug raw materials for Covid-19 treatment and prophylaxis gain value. With the widespread use of plant culture in the world and its use as a pharmaceutical raw material, the use of domestic herbal resources, especially in the industrial field, has been paved in our country. The most prominent and researched properties of medicinal plants are their use for therapeutic purposes. Herbal therapy is applied under different names such as phytotherapy, complementary and integrative medicine, traditional and herbal therapy in many countries around the world.
Due to its geographical location and climatic characteristics, Turkey has a wide variety of plant species. The role of medicinal plants in the treatment of diseases and protection of health as therapeutic alternatives is rapidly progressing worldwide and in our country. It is known how important plants are for human health and that they have been cherished since the earliest times of human history at the point of healing diseases. Turkey is one of the leading countries in the cultivation of medicinal and aromatic plants. Medicinal and aromatic plants are an important part of this richness in Turkey, which has a great richness with over 11 thousand plant diversity.
Supported within the scope of the strategic objective of “Development of Vaccine and Medicines for Covid-19” numbered 18AG020, prepared under the direction of TUBITAK Marmara Research Center, within the scope of TUBITAK Center of Excellence Support Program (1004 ), our university, International Faculty of Medicine Faculty Member, part of the SABITA, Center of Drug Discovery and Development Assoc. Dr. Mustafa Guzel and his team especially PhD student Kubra Dogan worked as a project researcher. The project, carried out in partnership with Istanbul Medipol University, Yildiz Technical University, Bahcesehir University and TUBITAK MAM Genetics team, was supported by TUBITAK Development of Vaccine and Medicines for Covid-19 Platform.
Based on the literature, among these natural plants Artemisia annua L. shows some promise for the treatment of SARS-CoV-2. The main objective of our study was to determine artemisinin content by LC-ESI-MS/MS, to investigate the in vitro biological activity of the Artemisinin from the A. annua plants grown in Turkey with various extracted methods, to elaborate in silico activity against SARS-CoV-2 using molecular modelling.
Therefore, in our study we selected the most accurate and efficient extraction method which is aimed to be applicable to the industrial scale. This research was later supported by in silico molecular modelling as well as in vitro biological activity studies. Our aim and objective were to identify the best extraction method for artemisinin and subsequently investigate its antiviral properties with pseudoneutralization assay and compare artemisinin binding motifs with known antivirals which is not appeared in the recent literature.
Chinese scientist Youyou Tu won the 2015 Nobel Prize in Medicine for an effective drug against malaria, developed from the Artemisia annua plant with Artemisic active ingredient. The plant has been extensively researched for plasmodium and its use in this field has spread worldwide. Artemisinin, one of the active components of the plant, has antiviral, anti-inflammatory, antiparasitic, antiallergic, antifibrotic, antiarrhythmic, immunomodulatory, antitumor, and cytotoxic effects. The main component of A. annua is artemisinin in the sesquiterpenlactone structure. Dihydroartemisinin, artemether, artesunat, artemisone, which are semi-synthetic derivatives of artemisinin, are included in the content of leading antimalarial drugs.
The novelty and advantage of our research from the literature:
Our team’s work has been recently accepted for publication in the Q1-SCI indexed journal, Phytochemical Analysis. (https://doi.org/10.1002/pca.3088). We are truly honored to be part of this research to help people in the treatment of Covid-19 and will continue to participate and contribute to produce good quality work of science in our country.
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