Green Chemistry: Opportunity in Drug Discovery Research (Part 2) (original) (raw)

Current Organic Chemistry

In continuation to part-1 of the thematic issue titled "Green Chemistry: Opportunity in Drug Discovery Research" [1], we are extremely happy to present the second part of this thematic issue. It would also include the review articles authored by researchers and academicians from across the world on different synthetic methodologies developed following the principles of green chemistry. Humankind has tirelessly engaged themselves in the innovation of new materials and technologies which could meet their steady demand and provide comfortable lives. Apart from meeting the basic needs, the advancement in the realm of science and technologies was indispensable to effectively cope with the challenges of both natural as well as artificial origin. In particular, chemists have always been passionate about the synthesis of chemicals of diverse varieties of structurally simple-to-complex nature. These scientific efforts led to the development of a vast range of compounds having immense importance in the areas of medicinal and material sciences. Although our scientific endeavor led to the discovery of several lifesaving drugs, natural products, polymers, and materials that made our life very comfortable and safe, still further investigation needs to be made, especially in the field of drug discovery in order to overcome the ongoing health crisis also due to COVID-19 pandemic and such future challenges [2]. The journey towards the synthesis of diverse varieties of compounds having immense application began as early as in 1828 when Friedrich Wöhler, a German chemist, first synthesized urea in the laboratory and discarded the vital force theory [3]. Since then, profound development has been made in the area of synthesis. Some major issues began surfacing that include rapid loss of natural resources, pollution, and also the safety of the person who is directly or indirectly involved in the development of any such chemical processes and technology. To overcome these challenges, specifically due to chemical synthesis, concepts of twelve principles of green chemistry were put forward by Prof. Paul T. Anastas and John C. Warner [4]. These principles mainly focus on the minimization or complete prevention of waste generation to avoid their deleterious effect on the lives and environment. In addition to that, other factors such as their storage, disposal, recycling etc., also add to the overall cost of the desired materials. It is important to highlight that the pharmaceutical industries occupy the top slot in terms of the amount of waste generation. Therefore, greener strategies need to be developed and employed in the synthesis of several other active pharmaceutical ingredients. To minimize and avoid waste generation, the importance of the 'Atom Economy', a term first introduced by B. M. Trost [5], was underlined in the second principle, which emphasizes the maximum incorporation of all the atoms of the reactants into the desired product so that the contribution of the reactants in waste generation could be avoided. Therefore, the inclusion of reactions with a high % atom economy such as cycloaddition, hydrogenation, carbonylation, hydroformylation, etc. is highly encouraged, especially in the case of multi-step synthetic schemes. Although other parameters such as Environmental factor' or 'E factor' introduced by R. A. Sheldon in late 1980 [6], is also required to assess the greenness of any chemical reaction as the % value of atom economy doesn't reflect the contribution of other auxiliary materials to the overall waste generation. It is important to mention that higher and lower values of % atom efficiency and E factor respectively could not be considered as the primary parameters to evaluate the efficiency and greenness of a method. Other aspects such as the toxicity associated with the reactants, reagents, intermediates, and the product formed in the reactions also need to be reviewed while designing any synthetic schemes. Therefore, taking all these facets into account, the third principle emphasizes 'less hazardous synthesis of chemicals' as by reducing the use of hazardous chemicals, the risk associated with a method can also be minimized or avoided. The fourth principle mainly focuses on the 'design of safer chemicals', which simply means that while attempting to enhance the efficacy of any chemicals, the attention should also be on the minimization of toxicity. For example, different aspects such as pharmacokinetics, pharmacodynamics, toxicity profile, ADME properties etc. of a prospective drug molecule could easily be predicted under in silico approach which minimizes the chances of their failure at the later stages of the trial [7]. Another important aspect that has been underlined in the fifth principle is the safe use of auxiliary substances, which mainly include solvents or separating agents. Although sometimes the use of solvent becomes indispensable as this influences several important factors of a reaction such as a homogeneity, mass transfer, reaction temperature, reaction kinetics etc. Despite such an excellent role of solvents, their adverse impact on the environment and human health has become a matter of serious concern for the past several decades. Therefore, to address these issues, the development of solvent-free reaction protocols is highly appreciated. In addition, the application of environmentally benign and safer alternatives such as water, ionic liquid, supercritical CO 2 , Polyethylene Glycol (PEG), fluorous biphasic systems have been encouraged [8]. To address the rising energy crisis, the next principle emphasizes on the development of energy-efficient processes as higher energy consumption contributes towards the higher price of the product and at the same time imposes adverse effect on the environment. Similarly, to address such energy challenges in the future, designing of reaction protocols employing microwave, UV-Visible radiations, sound wave, electrical energy, etc. are being encouraged as the energy loss could effectively be minimized, which otherwise would have been lost due to conventional thermal heating for extended time [9]. In addition to the energy, extensive use of nonrenewable sources such as petroleum-derived chemicals and solvents are posing a greater challenge for the future generation. Therefore, to achieve the goal of sustainable growth, the seventh principle emphasizes the use of renewable raw materials or feedstock. Some of the best renewable sources are products that can be derived from plants are cellulose, starch, suberin, lignin, polyhydroxyalkanoates, chitin, lactic acid, glycerol, and oils [10]. Therefore, the use of this natural renewable livestock may be encouraged. In general, protection and deprotection