Effect of Ionic Liquids on Mechanical, Physical, and Antifungal Properties and Biocompatibility of a Soft Denture Lining Material.

This study aims to evaluate the effect of ionic liquids and their structure on the mechanical (tensile bond strength (TBS) and Shore A hardness), mass change, and antifungal properties of soft denture lining material. Butyl pyridinium chloride (BPCL) and octyl pyridinium chloride (OPCL) were synthesized, characterized, and mixed in concentrations ranging from 0.65-10% w/w with a soft denture liner (Molloplast-B) and were divided into seven groups (C, BPCL1-3, and OPCL1-3). The TBS of bar-shaped specimens was calculated on a Universal Testing Machine. For Shore A hardness, disc-shaped specimens were analyzed using a durometer. The mass change (%) of specimens was calculated by the weight loss method. The antifungal potential of ionic liquids and test specimens was measured using agar well and disc diffusion methods (p ≤ 0.05). The alamarBlue assay was performed to assess the biocompatibility of the samples. The mean TBS values of Molloplast-B samples were significantly lower (p ≤ 0.05) for all groups except for OPCL1. Compared with the control, the mean shore A hardness values were significantly higher (p ≤ 0.05) for samples in groups BPCL 2 and 3. After 6 weeks, the OPCL samples showed a significantly lower (p ≤ 0.05) mass change as compared to the control. Agar well diffusion methods demonstrated a maximum zone of inhibition for 2.5% OPCL (20.5 ± 0.05 mm) after 24 h. Disc diffusion methods showed no zones of inhibition. The biocompatibility of the ionic liquid-modified sample was comparable to that of the control. The addition of ionic liquids in Molloplast-B improved the liner's surface texture, increased its hardness, and decreased its % mass change and tensile strength. Ionic liquids exhibited potent antifungal activity.

N-Arylacetamide derivatives of methyl 1,2-benzothiazine-3-carboxylate as potential drug candidates for urease inhibition.

Urease enzyme is an infectious factor that provokes the growth and colonization of virulence pathogenic bacteria in humans. To overcome the deleterious effects of bacterial infections, inhibition of urease enzyme is one of the promising approaches. The current study is designed to synthesize new 1,2-benzothiazine-N-arylacetamide derivatives 5(a-n) that can effectively provide a new drug candidate to avoid bacterial infections by urease inhibition. After structural elucidation by FT-IR, proton and carbon-13 NMR and mass spectroscopy, the synthesized compounds 5(a-n) were investigated to evaluate their inhibitory potential against urease enzyme. In vitro analysis against positive control of thiourea indicated that all the synthesized compounds have strong inhibitory strengths as compared to the reference drug. Compound 5k, being the most potent inhibitor, strongly inhibited the urease enzymes and revealed an IC50 value of 9.8 ± 0.023 µM when compared with the IC50 of thiourea (22.3 ± 0.031 µM)-a far more robust inhibitory potential. Docking studies of 5k within the urease active site revealed various significant interactions such as H-bond, π-alkyl with amino acid residues like Val744, Lys716, Ala16, Glu7452, Ala37 and Asp730.

Evaluating the Impact of Cellulose Extraction via Traditional and Ionosolv Pretreatments from Domestic Matchstick Waste on the Properties of Carboxymethyl Cellulose.

Carboxymethyl cellulose (CMC) is a hydrophilic derivative of cellulose whose large volumes have been used in textile processing, protective coatings, detergents, papers, and drilling fluids, while cellulose gum, which is the purified form of CMC, has extensive applications in food, cosmetic, and pharmaceutical industries. Therefore, this work reflects the production of CMC by extracting cellulose with traditional and ionosolv methods from domestic matchstick waste, providing an in-depth view of the overall process where two different kinds of cellulose were obtained from two different pretreatments, and the influence of cellulose on the profile of CMC was checked. All of the procedures have been performed under optimized conditions to reduce the cost and maximize the productiveness. The results depict that cellulose extracted by the ionosolv method using a protic ionic liquid, tetramethylguanidinium hydrogen sulfate (TMG-HSO4), is more degraded than that extracted by the traditional sulfide method using sodium sulfide (Na2S) and sodium hydroxide (NaOH). Thus, the produced CMC-2 via ionic liquid-extracted cellulose has more yield, DS (2.3), purity (98.5%), and solubility with less salt and moisture contents than CMC-1 produced by the conventional method due to an effective substitution of the hydroxyl group by the carboxymethyl group. Further, instrumental analyses like FTIR, XRD, 1H NMR, 13C NMR, and SEM emphasize the results that CMC-2 has more reduction of the hydroxyl peak in FTIR, a more amorphous structure in XRD, intense peaks in NMR, and the roughness of the surface in SEM.

Carboxymethyl cellulose-based materials as an alternative source for sustainable electrochemical devices: a review.

In electrochemistry, bio-based materials are preferred over the traditional costly and synthetic polymers due to their abundance, versatility, sustainability and low cost. One of the bio-based polymers is carboxymethyl cellulose (CMC) which has become an overarching material in electrochemical devices pertaining to its amphiphilic nature with multi-carbon functional groups. Owing to its flexible framework with fascinating groups on its surface like hydroxide (-OH) and carboxylate (-COO-), CMC is able to be modified into conducting materials by blending it with other biopolymers, synthetic polymers, salts, acids and others. This blending has improved the profile of CMC by exploiting the ability of hydrogen bonding, swelling, adhesiveness and dispersion of charges and ions. These properties of CMC have made it possible to utilize this bio-sourced polymer in several applications as a conducting electrolyte, binder in electrodes, detector, sensor and active material in fuel cells, actuators and triboelectric nanogenerators (TENG). Thus, CMC based materials are cheap, environment friendly, hydrophilic, biodegradable, non-toxic and biocompatible which render it a desirable material in energy storage devices.

An overview of biomedical applications of choline geranate (CAGE): a major breakthrough in drug delivery.

A number of studies are on the way to advancing the field of biomedical sciences using ionic liquids (ILs) and deep eutectic solvents (DESs) in view of their unique properties and inherent tunability. These significant solvents tend to enhance the physical properties of the drug, increase their bioavailability and promote the delivery of recalcitrant drugs to the body. One such widely investigated tempting multipurpose IL/DES system is choline geranate (CAGE), which has gained significant interest due to its biocompatible and highly potent antiseptic behavior, which also facilitates its sanitizing ability to combat the coronavirus. This review focuses on total advancements in biomedical applications of CAGE. This biocompatible IL/DES has made facile the solubilization of hydrophobic and hydrophilic drugs and delivery of intractable drugs through physiological barriers by stabilizing proteins and nucleic acids. Therefore, it has been used as a transdermal, subcutaneous, and oral delivery carrier and as an antimicrobial agent to treat infectious diseases and wounds as approved by laboratory and clinical translations. Moreover, current challenges and future outlooks are also highlighted to explore them more purposefully.

Green synthesis of coumarin derivatives using Brønsted acidic pyridinium based ionic liquid [MBSPy][HSO4] to control an opportunistic human and a devastating plant pathogenic fungus Macrophomina phaseolina.

An eco-friendly simple protocol has been devised for the preparation of coumarin derivatives using doubly Brønsted acidic task specific ionic liquid (TSIL) as a catalyst. Solvent-free conditions were employed for the reaction of different substituted phenols with ß-ketoester in TSIL to produce corresponding substituted coumarin derivatives in good to excellent yields at ambient conditions; at room temperature and with reduced reaction times. The ionic liquid catalyst can be recycled and reused up to five times. All the synthesized coumarins were evaluated for their antifungal activities against Macrophomina phaseolina, a plant as well as an opportunistic human pathogenic fungus affecting more than 500 plant species worldwide and with no registered commercial fungicide available against it, to date. Amongst all the coumarins tested, compounds 3f and 3i showed excellent antifungal activity comparable to reference fungicide mancozeb. The current methodology provides an easy and expedient way to access the coumarin core in search of potential fungicides for sustainable agriculture.

Cost-Effective Processing of Carbon-Rich Materials in Ionic Liquids: An Expeditious Approach to Biofuels.

This work presents a cost-effective approach for processing of renewable carbon-rich biomass using pyridinium-based Lewis acidic ionic liquids (LAILs). Rice husk as carbon-rich lignocellulosic waste was pretreated with a series of neutral and Lewis acidic ionic liquids to yield valuable intermediate platform monosaccharides. Novelty in the work lies in direct conversion of lignocellulosic carbohydrates into reducing sugars without their further conversion into 5-hydroxymethylfurfural or any other platform chemicals that are fermentation inhibitors for bioethanol production. The unconverted cellulose-rich material (CRM) is regenerated as a delignified material by the simultaneous addition of antisolvents. CRM and recovered lignin obtained after pretreatment were analyzed via scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and Fourier transform infrared (FTIR) spectroscopy. The process was optimized with respect to a high yield of platform sugars and the quantity as well as quality of recovered CRM and lignin contents. Various reaction parameters involving the molecular structure of ionic liquids (ILs), Lewis acidic strength of ILs, biomass loading into IL, time, temperature, and biomass particle size were screened thoroughly. From all of the tested ILs, unsymmetrical 3-methylpyridinium IL having N-octyl substitution and chloroaluminate anion showed a greater conversion efficiency at 100 °C for 1.5 h. FTIR and SEM analyses of recovered CRM justify >90% lignin removal from rice husk. From all of the removed lignin, 60 wt % of original lignin content was recovered. The Lewis acidic system possessed recycling ability up to 3 times for subsequent treatment of rice husk without a significant loss of efficiency.

Evaluating the Effect of Ionic Liquid on Biosorption Potential of Peanut Waste: Experimental and Theoretical Studies.

Peanut skin having polyphenols as major constituents is a natural, abundant, and environmentally friendly potent biosorbent for aquatic pollutants such as heavy metals. Its natural potential can be enhanced several times by treating it with ionic liquids-the green solvents. This report presents a complete study on biosorption of divalent cadmium ions using ionic liquid-treated peanut skin. Initially, both peanut biomasses, skin and shells, were tested, and peanut skin was used for thorough experimentation because of its higher adsorption potential (q e values). Ionic liquids are highly green and designed solvents with vast adjustable striking features such as high thermal and chemical stability, insignificant vapor pressure, wide electrochemical assortment, non-volatility, non-flammability, less toxicity, and high recycling ability. Peanut skin after treatment with ionic liquids was characterized via FTIR, TGA, SEM, and XRD. The biosorption process was optimized with respect to time, temperature, metal ion concentrations, agitation speed, pH, and adsorbent dose. Data obtained were interpreted by kinetic, isothermal, and thermodynamic models. The biosorbent and ionic liquid both are regenerated and recycled up to three times, so cost effectiveness is a promising thing.

Enhancing catalytic potential of gold nanoparticles by linear and cross-linked polyurethane blending.

This work describes the synthesis of gold nanoparticles (AuNPs) and their subsequent stabilization using a water-borne polyurethane matrix of micro-particles (Au/PU) by a heating method. Composites were prepared both from linear and cross-linked polyurethane (LPU and CPU). Catalytic activities of synthesized composites exhibiting 226.4 nm size were evaluated for reduction of Congo red dye. More than 90% Congo red degradation was achieved in just 6 minutes with Au/LPU. Under similar conditions, 30% of dye was degraded with Au/CPU composite in 5 minutes. The effects of different variables such as concentration of dye, catalyst dose and concentration of reagents have been optimized. The degradation process followed first order kinetics. The most efficient composite (Au/LPU) was characterized using UV/Vis, FTIR, SEM, XRD and DLS techniques. The excellent catalytic activity can be attributed to the polyurethane matrix making the dye available to catalytic sites (AuNPs).

Green synthesis of gold nanoparticles from Manilkara zapota L. extract and the evaluation of its intrinsic in vivo antiarthritic potential.

The plant Manilkara zapota belongs to the family Sapotaceae and is commonly known as Chiku in Pakistan. Traditionally, M. zapota is used in pulmonary diseases, diarrhea, rheumatism, hemorrhage, and ulcers. There is no study available on the in vivo antiarthritic activity of M. zapota and its gold nanoparticles (AuNPs). The aim of this study is to evaluate the in vivo acute and sub-acute antiarthritic activity of aqueous extract of M. zapota and its biosynthesized gold nanoparticles (AuNPs). Plant-induced reduction method was used for the synthesis of AuNPs. The synthesized AuNPs were characterized via UV, FTIR, SEM, and zeta potential measurements and were optimized by screening various parameters including time, temperature, pH, and salt concentration. Arthritis in rats was induced by Freund's Complete Adjuvant (FCA) injection in hind paw. The antiarthritic effect was evaluated by the determination of paw volume, joint diameter, latency time, hematological, biochemical parameters, antioxidant biomarkers, TNF-α level, and radiological evaluation. The aqueous extract and nanoparticles significantly decreased the paw volume, joint diameter, and significantly increased latency time as compared to the FCA-induced arthritic group. They significantly normalized the hematological, biochemical parameters, and oxidative stress biomarkers in comparison to the arthritic group. They also significantly decreased the TNF-α level when assessed against the arthritic group. Radiological evaluation confirmed the antiarthritic effect of the aqueous extract and nanoparticles of M. zapota leaf extract. It is concluded that the aqueous extract and nanoparticles of M. zapota possess significant analgesic, antiarthritic, and anti-inflammatory activity. However, nanoparticles possess more pronounced antiarthritic activity as compared to the aqueous extract. Moreover, free radical scavenging action and TNF-α reduction showed a prominent role in their antiarthritic activity. Further, investigation is underway to identify the active phytochemical constituent responsible for the antiarthritic activity.

Evaluating the potential of a novel hardwood biomass using a superbase ionic liquid.

Lignocellulosic biomass, being ubiquitous and easily accessible, bears a huge potential for sustainable energy and other products. Fractionation, delignification, and subsequent utilization of hardwood biomass has been ever challenging for a bio-based refinery. Acacia nilotica (kikar in local language) is a hardwood tree commonly found in Pakistan, where its abundance owes to favorable and benign environmental conditions. Ionic liquids based on superbase "tetramethylguanidine (TMG)" are green solvents that are found to be good cellulose processing agents. Previously, TMG-based protic ionic liquids (PILs) have been used for cellulose processing and transformation into value-added products. In this study, an ionic liquid comprising a tetramethylguanidinium cation and a hydrogen sulfate anion was employed for the evaluation of the potential of acacia for fermentable sugars and lignin. Pretreatment was carried out at 100, 120, and 140 °C for 0.5, 1, 2 and 4 hours. The results indicate that [TMG][HSO4] is an efficient delignifying agent affording 81% lignin removal and 76% sugar yield by subsequent enzymatic hydrolysis. The evaluation of the efficiency of IL and the biomass was verified by compositional analysis, FT-IR, HSQC, and SEM analyses.

Exploring synthetic and therapeutic prospects of new thiazoline derivatives as aldose reductase (ALR2) inhibitors.

Inhibition of aldose reductase (ALR2) by using small heterocyclic compounds provides a viable approach for the development of new antidiabetic agents. With our ongoing interest towards aldose reductase (ALR2) inhibition, we have synthesized and screened a series of thiazoline derivatives (5a-k, 6a-f, 7a-1 & 8a-j) to find a lead as a potential new antidiabetic agent. The bioactivity results showed the thiazoline-based compound 7b having a benzyl substituent and nitrophenyl substituent-bearing compound 8e were identified as the most potent molecules with IC50 values of 1.39 ± 2.21 µM and 1.52 ± 0.78 µM respectively compared with the reference sorbinil with an IC50 value of 3.14 ± 0.02 µM. Compound 7b with only 23.4% inhibition for ALR1 showed excellent selectivity for the targeted ALR2 to act as a potential lead for the development of new therapeutic agents for diabetic complications.

Multicomponent reactions (MCR) in medicinal chemistry: a patent review (2010-2020).

Introduction: Multicomponent reactions (MCR) has been utilized to synthesize a vast range of analogs belonging to diverse classes of heterocyclic compounds offering multidimensional pharmaceutical applications. The unique feature of MCR includes the synthesis of highly functionalized molecules in a single pot to build quick libraries of compounds of biological interest to identify new leads as potential therapeutic agents.Area covered: The current review article covers the patents published in the last decade in order to highlight the importance of multicomponent reactions for synthesizing complex-functionalized molecules of high biological significance.Expert opinion: Easily automated one-pot multicomponent reactions (MCRs) has demonstrated successful impact at different stages of the lead discovery, lead optimization, and pre-clinical process development arenas. Application of MCRs is the recent advancement in the field of drug design and discovery which will expectedly lead to the development of medicinally important heterocyclic compounds with a vast range of biological activities.

Extraction of basil seed mucilage using ionic liquid and preparation of AuNps/mucilage nanocomposite for catalytic degradation of dye.

Basil seeds are widely cultivated throughout the world because of their extensive applications in various fields of life. The Basil seeds mucilage (BSM) exhibits remarkable physical and chemical properties like high water absorbing capacity, emulsifying, and stabilizing properties. The extraction of this mucilage from the seed surface has always been done by physical and chemical methods, which has certain drawbacks. Here, we report for the first time a chemical method for the effective extraction of this mucilage using ionic liquids (ILs); the green solvents. Pyridinium chloride based ILs were investigated for the effective extraction of mucilage and the process was optimized for various variables i.e. time, temperature, basil seed loading, co-solvents, anti-solvents. The extraction yield (up to 25% w/w of mucilage per basil seeds dry weight) was obtained at optimum conditions. Extracted mucilage was characterized by analytical techniques. The extracted BSM was used to prepare AuNps/BSM nanocomposite by stabilizing the gold nanoparticles. The AuNps/BSM nanocomposite was applied for the catalytic degradation of dyes (congo red; 12 min, methyl orange; 4 min, whereas 4-nitrophenol; 6 min).

One-Pot Deconstruction and Conversion of Lignocellulose Into Reducing Sugars by Pyridinium-Based Ionic Liquid-Metal Salt System.

Constantly decreasing fossil resources and exceeding energy demands are the most alarming concerns nowadays. The only way out is to develop efficient, safe, and economical biomass processing protocols that can lead toward biofuels and fine chemicals. This research is one of such consequences involving the deconstruction and conversion of wheat straw carbohydrate constituents into reducing sugars via one-pot reaction promoted by Lewis acidic pyridinium-based ionic liquids (PyILs) mixed with different metal salts (MCl). Various parameters such as the type of metal salt, loading amount of metal salt, time, temperature, particle size of biomass, and water content which affect the deconstruction of wheat straw have been evaluated and optimized. Among the studied ionic liquid (IL) and metal salt systems, the best results were obtained with [BMPy]+ CoCl 3 - . The dinitrosalicylic acid (DNS) assay was used to determine the percentage of total reducing sugars (TRS) generated during treatment of wheat straw. The deconstructed wheat straw was characterized with various analytical tools, that is, Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and X-ray powder diffraction (XRD) analyses. The IL-metal salt system was recycled for subsequent treatment of wheat straw. Statistical parameters were calculated from analysis of variance (ANOVA) at the 0.05 level of confidence.

Extraction of lignin and quantitative sugar release from biomass using efficient and cost-effective pyridinium protic ionic liquids.

Lignocellulosic biomass is enormously abundant around the globe. It bears huge potential for renewable products as its components can be converted to many useful products via cheaper processes. Recently, the component of biomass that has attracted enormous attention is lignin owing to its several aromatic or phenolic constituents. The utilization of lignin, however, is hindered by its troublesome separation mainly due to the difficult nature of the lignocellulosic biomass. Protic ionic liquids have great potential for extraction of lignin from the lignocellulosic biomass to make it viable for various transformations. In this study, protic ionic liquids comprising a pyridinium cation and a dihydrogen phosphate anion (H2PO4 -) were prepared and used for lignin extraction and subsequent saccharification of the cellulose pulp. The ILs exhibited appreciably high lignin yields (optimum 73%) under mild conditions (100 °C) and shorter time (2 h). Fairly good sugar (glucose) yields (77%) verify effective delignification. The analysis of ILs and biomass was accomplished by H-NMR, FT-IR, SEM, HSQC and GPC.

Exploring antidiabetic potential of adamantyl-thiosemicarbazones via aldose reductase (ALR2) inhibition.

The role of aldose reductase (ALR2) in diabetes mellitus is well-established. Our interest in finding ALR2 inhibitors led us to explore the inhibitory potential of new thiosemicarbazones. In this study, we have synthesized adamantyl-thiosemicarbazones and screened them as aldehyde reductase (ALR1) and aldose reductase (ALR2) inhibitors. The compounds bearing phenyl 3a, 2-methylphenyl 3g and 2,6-dimethylphenyl 3m have been identified as most potent ALR2 inhibitors with IC50 values of 3.99 ±â€¯0.38, 3.55 ±â€¯0.26 and 1.37 ±â€¯0.92 µM, respectively, compared with sorbinil (IC50 = 3.14 ±â€¯0.02 µM). The compounds 3a, 3g, and 3m also inhibit ALR1 with IC50 value of 7.75 ±â€¯0.28, 7.26 ±â€¯0.39 and 7.04 ±â€¯2.23 µM, respectively. Molecular docking was also performed for putative binding of potent inhibitors with target enzyme ALR2. The most potent 2,6-dimethylphenyl bearing thiosemicarbazone 3m (IC50 = 1.37 ±â€¯0.92 µM for ALR2) and other two compound 3a and 3g could potentially lead for the development of new therapeutic agents.

A patent update on therapeutic applications of urease inhibitors (2012-2018).

INTRODUCTION: Urease is a nickel-containing metalloenzyme that is commonly found in different bacteria, plants, algae, and fungi and mediates the growth of many pathogenic bacteria in the acidic environment of the stomach. Despite the large number of molecules known to have excellent urease inhibitory activity, there is an alarming lack of urease inhibitor drugs on the market. AREAS COVERED: This review aims to provide a comprehensive overview of the different types of molecules patented as potent urease inhibitors from the year 2012 to 2018. EXPERT OPINION: Urease is an important target to treat urease-related bacterial infections manifesting as gastric ulcers, urinary tract infections, and kidney stones. Although many different molecules as inhibitors of urease have been reported, only a few have advanced to clinical trials. The development of new effective urease inhibitors demands new suitable lead molecules. This review covers the patents on urease inhibitors in recent years (2012-2018) with a hope to bring into focus the issue and need for availability of new urease inhibitors on the market.

Benzoxazinone-thiosemicarbazones as antidiabetic leads via aldose reductase inhibition: Synthesis, biological screening and molecular docking study.

Aldose reductase is an important enzyme in the polyol pathway, where glucose is converted to fructose, and sorbitol is released. Aldose reductase activity increases in diabetes as the glucose levels increase, resulting in increased sorbitol production. Sorbitol, being less cell permeable tends to accumulate in tissues such as eye lenses, peripheral nerves and glomerulus that are not insulin sensitive. This excessive build-up of sorbitol is responsible for diabetes associated complications such as retinopathy and neuropathy. In continuation of our interest to design and discover potent inhibitors of aldo-keto reductases (AKRs; aldehyde reductase ALR1 or AKR1A, and aldose reductase ALR2 or AKR1B), herein we designed and investigated a series of new benzoxazinone-thiosemicarbazones (3a-r) as ALR2 and ALR1 inhibitors. Most compounds exhibited excellent inhibitory activities with IC50 values in lower micro-molar range. Compounds 3b and 3l were found to be most active ALR2 inhibitors with IC50 values of 0.52 ±â€¯0.04 and 0.19 ±â€¯0.03 µM, respectively, both compounds were more effective inhibitors as compared to the standard ALR2 inhibitor (sorbinil, with IC50 value of 3.14 ±â€¯0.02 µM).

Quinazoline and quinazolinone as important medicinal scaffolds: a comparative patent review (2011-2016).

INTRODUCTION: Quinazoline and quinazolinone scaffolds represent an important class of biologically active nitrogen heterocyclic compounds. A variety of marketed drugs are based on these moieties. A diverse range of molecules with quinazoline/quinazolinone moieties have been reported to exhibit broad spectrum of biological activities. AREAS COVERED: This review covers recent efforts in the synthesis and biological screening of quinazoline/quinazolinone based compounds from 2011-2016. EXPERT OPINION: Quinazoline and quinazolinones represent a diverse class of biologically active nitrogen heterocyclic compounds with immense therapeutic potential. Their ease of synthetic accessibility, and flexibility in structural modifications and functionalization further adds to their appeal in medicinal chemistry. A number of currently available drugs are based on quinazoline/quinazolinone scaffold. It is interesting to note that, among the recent patents available, a lot of them focus on the promising anticancer activity of quinazoline and quinazolinone containing compounds. However their biological activity is certainly not limited to anticancer only, they are also known to elicit a number of other biological and physiological effects in vitro and in vivo respectively. The interest in quinazolines and quinazolinones is ever growing, since they offer a fairly diverse chemical space for exploration of medicinal potential.