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Why Prodrugs and Propesticides Succeed John E. Casida Chem. Res. Toxicol., Just Accepted Manuscript • DOI: 10.1021/acs.chemrestox.7b00030 • Publication Date (Web): 23 Mar 2017 Downloaded from http://pubs.acs.org on March 26, 2017

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Chemical Research in Toxicology

Why Prodrugs and Propesticides Succeed

John E. Casida

Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy, and Management, University of California, Berkeley 94720, United States

ACS Paragon Plus Environment


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ABSTRACT: What are the advantages of bioactivation in optimizing drugs and pesticides? Why are there so many prodrugs and propesticides? These questions are examined here by considering compounds selected on the basis of economic value or market success in 2015. The 100 major drugs and 90 major pesticides are divided into ones acting directly and those definitely or possibly requiring bioactivation. Established or candidate prodrugs accounted for 19% of the total drug sales with corresponding values of 20, 37 and 17% for proinsecticides, proherbicides and profungicides. The 19 prodrugs acting in humans generally had better pharmacodynamic/pharmacokinetic properties for target enzyme, receptor, tissue or organ specificity due to their physical properties (lipophilicity and stabilization). Bioactivation usually involved hydrolases or CYP oxidation or reduction. Prodrugs considered are: neuroactive aripiprazole, eletriptan, desvenlafaxin, lisdexamfetamine, quetiapine, and fesoterodine; cholesterol-lowering atorvastatin, ezetimibe and fenofibrate; various prodrugs activated by esterases or sulfatases, ciclesonide, oseltamivir, dabigatran; omega-3 fatty acid ethyl esters and esterone sulfate; and five others with various targets (sofosbuvir, fingolimod, clopidogrel, dapsone and sildenafil). The proinsecticides are the neuroactive chlorpyrifos, thiamethoxam, and indoxacarb, two spiro enol ester inhibitors of acetyl CoA carboxylase (ACCase) and the bacterial protein delta-endotoxin. The proherbicides considered are five ACCase inhibitors including pinoxaden and clethodim, three protox inhibitors (saflufenacil, flumioxazin and canfentrazone-ethyl) and three with various targets (fluroxypyr, isoxaflutole and clomazone). The profungicides are prothioconazole, mancozeb, thiophanate-methyl, dazomet and fosetyl-aluminum. The prodrug and propesticide concept is broadly applicable and has created some of the most selective pharmaceutical and pest control agents illustrated here by major compounds that partially overcome pharmacokinetic limitations of potency and selectivity in the corresponding direct-acting compounds. The


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challenges of molecular design extend beyond the target site fit to the bioactivatable precursor and the fascinating chemistry and biology matched against the complexity of life processes.



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CONTENTS Introduction Prodrugs Neuroactive Cholesterol-lowering Others Proinsecticides Neuroactive ACCase Pore-forming Proherbicides ACCase PPO Others Profungicides 14α-Demethylase Others Paths to Success Author Information Note Biography Acknowledgements Abbreviations References

INTRODUCTION Drugs and pesticides are discovered, developed and used as selective agents for specific targets among the multitude of possible processes, systems and organisms. Several factors differentiate drugs from pesticides. Drugs are usually for individual people to cure a physiological or infectious disease. Pesticides are generally applied to control an insect, weed, or fungal pest population in an environmental system. Selectivity for drugs is between organs, tissues and cells and for pesticides is between organisms. Selection for resistance is rare for drugs relative to pesticides. Drug interactions must be carefully considered since exposure to one drug or chemical can induce or inhibit the targets or detoxification systems for other chemicals. The practitioners for prescribing or delivering drugs (often MDs) are better trained in chemistry than most of those advising or applying pesticides (biologists and agriculturalists). Drugs enter the human body by ingestion, dermal absorption or inhalation under controlled circumstances. Pests are protected from the environment by the cuticle for insects, the leaf waxes for plants and the cell wall for fungi, barriers that must be crossed for toxicant action. The types of formulations are usually very different for drugs and pesticides.


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Many major drugs and pesticides are actually prodrugs and propesticides with protective substituents to improve pharmacodynamics/pharmacokinetics, chemical stability, selective toxicity and environmental safety. This review considers bioactivations and mechanisms of the prodrugs and propesticides among the 100 major drugs1 and 90 major insecticides, fungicides and herbicides2. They are bioactivated usually by oxidases and hydrolases to the ultimate active agents that inhibit a great variety of metabolic processes. Bioactivation in the present context normally refers to conversion in significant amounts to metabolite(s) as active or more active than the parent compound on the primary target of the drug or pesticide in people or pests. This makes a vast area of knowledge covering hundreds of drugs and more than a thousand pesticides. Many of them are prodrugs or propesticides, which are considered together here by restricting the selection to the 100 major drugs1 and 30 major pesticides for each of insecticides, herbicides and 2 fungicides . This leaves 19 prodrugs and 22 propesticides of widely varied bioactivations and mechanisms, the subject of this review (Table 1). Further information on each compound is given in the cited references, in the Merck Index3, the Pesticide Manual4 and registration documents of national and international organizations.



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Table 1. Major Prodrugs and Propesticides and Their Molecular Targets, Bioactivation Mechanisms, Control Features and Annual Sales


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a

b

Data are U.S. sales for prescribed branded drugs1 and global sales for pesticides2. Spiromesifen controls whiteflies and mites and delta-endotoxin controls lepidopterous larvae, mosquito larvae and coleopteran pests.



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PRODRUGS 5-7

Neuroactive (Figure 1). Aripiprazole (1) is an atypical antipsychotic drug acting as a dopamine D2 receptor partial agonist. It is also a partial 5-hydroxytryptamine (5-HT)1A agonist and 5-HT2A antagonist. The only known active metabolite is dehydroaripiprazole (1A) formed by CYP2D6 and CYP3A4 and providing exceptionally long action. Metabolism also involves hydroxylation and Ndealkylation. Eletriptan (2)8-10 with indole and phenylsulfonyl substituents is a 5-HT1B/1D receptor agonist with little or no action on adrenergic, dopaminergic, muscarinic or opiod receptors. It is used to treat migraine headaches and is transported by P-glycoprotein. The metabolite N-desmethyl-2 formed primarily by CYP3A4 is also active but appears at relatively low levels. Desvenlafaxine (3)11-13 is an antidepressant of the serotonin-norepinephrine transporter (SNT) or re-uptake inhibitor class and the first non-hormonal treatment of menopausal vasomotor symptoms. It is also found as the major active metabolite of venlafaxine (3A), an important antidepressant. Lisdexamfetamine dimesylate (4)14-16 is a central nervous system stimulant for attention-deficit hyperactivity (ADHD) and binge eating disorders. It acts as an amphetamine prodrug activated by an aminopeptidase to dextroamphetamine and L-lysine. The responsible amidase is present in the cytosol of red blood cells, providing the long daily duration of drug efficacy. Quetiapine (5),17-19 a dibenzothiazepine, is an atypical antipsychotic and antidepressant used to treat schizophrenia and bipolar disorder. Some of this activity is due to the active metabolite norquetiapine (5A) which inhibits the noradrenaline transporter (NET) and also acts as an agonist and antagonist on various 5-HT receptors. Fesoterodine (6)20-22 as a prodrug and 5-hydroxymethyl tolterodine as the active metabolite are potent muscarinic acetylcholine receptor (mAChR) antagonists for treatment of overactive bladder syndrome. The prodrug approach was necessary for systemic


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Figure 1. Major prodrugs. Compounds 1-6 are neuroactive, 7-9 are cholesterol-lowering, and 10-19 are other mechanisms. Arrows designate initial sites of metabolic attack leading to bioactivation. Subsequent reactions to form the ultimate bioactivation products are considered separately for individual compounds. bioavailability after oral administration. The bioactivation occurs via ubiquitous nonspecific plasma esterases. An alternative prodrug tolterodine, lacking the isobutyryl moiety and with methyl replacing hydroxymethyl, involves CYP2D6 genotype-dependent bioactivation and is more variable in effectiveness and safety20-22. Cholesterol-lowering (Figure 1). Atorvastatin (7)23-25 is a highly potent competitive inhibitor of 3hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and one of the most important statins in lowering cholesterol levels. The 2- and 4- hydroxy metabolites formed by CYP3A4 are equipotent to the parent 7 and are important contributers in the HMG-CoA reductase inhibition. Lactone-7A is considered to be a prodrug. Ezetimibe (8)26,27 and its active glucuronide metabolite are cholesterol absorption inhibitors that target Nieman Pick C1 like 1 (NPC1L1) protein-mediated uptake at the jejunal enterocyte brush border to lower low-density lipoprotein cholesterol (LDL-C). The glucuronide metabolite formed in the small intestine and liver is excreted in the bile back into the intestinal lumen where it again can inhibit



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the NPC1L1 protein. Fenofibrate (9)28-30 is the isopropyl ester prodrug for fenofibric acid that undergoes esteratic cleavage and carbonyl reduction to reduced fenofibric acid which is also pharmacologically active. The carboxylic acids are conjugated as glucuronides. Fenofibrate in vivo produces reductions in total cholesterol and lowers lipid levels by activating peroxisome proliferator – activated receptor alpha (PPARα) and lipoprotein lipase and reducing apolipoprotein CIII thereby increasing lipolysis and elimination of triglyceride-rich particles from plasma. Others (Figure 1). Several other types of prodrugs are activated by hydrolases. Ciclesonide (10), a glucocorticosteroid used as inhalation therapy for asthma, is bioactivated to desisobutyryl-ciclesonide by carboxylesterases in bronchial epithelial cells with subsequent reversible esterification with fatty acids as a storage pool. 30-33 Oseltamivir (11),34,35 marketed as Tamiflu, is an antiviral medication for flu acting as a neuraminidase inhibitor after esterase bioactivation to the carboxylic acid. Inhibition of neuraminidase expressed on the viral surface prevents release of the virions from the infected cells reducing the severity and duration of uncomplicated influenza. Dabigatran etexilate (12)36-38 is an anticoagulant acting after hydrolysis as a direct thrombin inhibitor for prevention of cardiac thromboembolism acute coronary syndrome. Dabigatran is not orally available because of the highly polar, zwitterionic nature and accordingly was developed as a prodrug. The glucuronide conjugates are also pharmacologically active. In the case of major dabigatran – induced bleeding the antidote idarucizumab is very effective and rapid in reversing the anticoagulation action. Omega-3 fatty acid ethyl esters (13)39,40 are one of the important standard treatments for hypertriglyceridemia. They require activation by esterases cleaving the C22docosahexaenoic and C20-eicosapentaenoic acid esters to the carboxylic acids as intermediates in 41,42 and other conjugated estrogens isolated from pregnant eicosanoid synthesis. Estrone sulfate (14) mare’s urine and designated premarin are used for the treatment of menopause symptoms. Sulfatase 43, 44 bioactivation is required for esterone sulfate action in formation of human bone. Sofosbuvir (15) is a nucleotide analog inhibitor of the RNA polymerase that hepatitis C virus uses to replicate its RNA. It is a phosphoramidate prodrug rapidly bioactivated by diphosphate kinase to the 5’-triphosphate (15A) which serves as a defective substrate for the NS5B protein (which is the viral RNA polymerase) thereby inhibiting viral RNA synthase. Fingolimod (16)45-47 derived from a fungal metabolite myriocin is a 2aminopropane-1,3-diol derivative with a 2-octylphenylethyl substituent. It acts as a sphingosine-1phosphate (S1P) receptor modulator with bioactivation on phosphorylation (16A) by sphingosine kinase in the cell. It sequesters lymphocytes in lymph nodes, preventing them from contributing to an antiimmune reaction, and is used in treating relapsing-remitting multiple sclerosis. Clopidogrel (17),48-52 a thienopyridine antiplatelet drug, binds to the platelet P2RY12 purinergic receptor, inhibiting ADPmediated platelet activation and aggregation. A two-step bioactivation involves CYP oxidation to the 2oxo derivative (17A) which undergoes hydrolysis to the active metabolite containing a thiol group that binds to a free cysteine on the P2RY12 receptor blocking its activation. Metabolism also involves rapid hydrolysis in vitro and in vivo to the inactive carboxylic acid derivative. Dapsone (18)53-55 is an antibiotic used for treatment of leprosy, pneumonia, and acne. It is a structural analog of p-aminobenzoic acid, and a competitive inhibitor of bacterial dihydropteroate synthase (DHPS) thereby blocking dihydrofolic acid synthesis. N-Hydroxy-18 produced by CYP2C19 is associated with methemoglobinema in mammals. Sildenafil (19)56-58 and N-desmethyl-19 inhibit cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). GMP and its metabolite levels elevated by endogenous nitric oxide released on sexual stimulation are maintained high by 19 and its N-desmethyl metabolite inhibition of PDE5 in the penis leading overall to its use in treating erectile dysfunction.


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PROINSECTICIDES Neuroactive (Figure 2). Chlorpyrifos (20),59,60 a trichloropyridinyl phosphorothionate, is the most important remaining acetylcholinesterase (AChE) inhibitor among the insecticides of the last 70 years. It undergoes CYP-dependent desulfuration to the active oxon (20A). The released sulfur results in a mechanism-based inactivation of CYP2B6. Thiamethoxam (21),61,62 a neonicotinoid, shares with imidacloprid the top position among insecticides, both acting as nicotinic acetylcholine receptor (nAChR) agonists. The effectiveness of 21 is due in part to N-demethylation to desmethyl-thiamethoxam (21A) or cleavage of the oxadiazine moiety from N-methylene hydroxylation leading to clothianidin (21B). The three active agents vary somewhat in specificity and persistence. Aldehyde oxidase serves as the nitroreductase. Indoxacarb (22),63-66 an oxadiazine insecticide, is bioactivated by esterase or amidase descarbomethoxylation to a potent voltage-dependent sodium channel blocker acting in insect nerve cells

at a site different than that for any other insecticide thereby circumventing target site cross resistance. The activation product is a major metabolite in insects but minor in mammals contributing to the selective toxicity. Figure 2. Major proinsecticides with important sites of metabolism and bioactivation shown by arrows.



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ACCase (Figure 2). Spiromesifen (23), an oxaspiro ester, and spirotetramat (24), an azaspiro ester, are two major cyclic keto-enol proinsecticides/proacaricides67-70 esteratically bioactivated to potent acetyl-CoA carboxylase (ACCase) inhibitors. The pKa value of around 5 for the activated forms allows them to be translocated downward via the phloem towards sucking pests feeding on the roots. The cyclic enols from cleavage bind to the carboxyl transferase domain coupled to ATP-dependent biotin carboxylation of acetyl-CoA in malonyl-CoA formation. They were developed from ACCase-inhibitor herbicides that act on a different binding site than the insecticides. 71,72 Pore-forming (Figure 2). Bacillus thuringiensis bacteria produce delta-endotoxins (25) (also called Cry toxins) used extensively in pest insect control as the proteins in spores or expressed in genetically-engineered crops. Following ingestion, these proteins are activated by the gut alkaline pH and proteolytic cleavage then bind to the epithelium forming cation-selective channels leading to cell lysis and death, i,e they are proinsecticides.

PROHERBICIDES ACCase (Figure 3). Four ACCase inhibitors73-77 are major ester herbicides esteratically-cleaved to the bioactivated acids following absorption into plants. They are the phenylpyrazoline pinoxaden (26), the aryloxyphenoxypropionate clodinafop-propagyl (27), and the aryloxyphenoxypropionates fenoxaprop-Pethyl (28) and fluazifop-P-butyl (29). These herbicides are primarily used for postemergence grass control in broadleaf crops with selectivity conferred by differences in ACCase sensitivity. The


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cyclohexanedioneoxime clethodim (30), also an ACCase inhibitor, is converted in part to sulfoxide and 78 sulfone metabolites, which are included in residue analyses. Figure 3. Major proherbicides with important sites of metabolism and bioactivation shown by arrows. PPO (Figure 3). Three major herbicides are potent inhibitors of protoporphyrinogen oxidase (PPO) blocking heme and chlorophyll biosynthesis resulting in endogenous accumulation of phytotoxic porphyrins and membrane disruption. They probably mostly act directly rather than as proherbicides. The pyrimidinedione saflufenacil (31)79-81 is more effective than its N-dealkylation metabolite but both are included in residue analyses. The N-phenyl cyclohexenedicarboximide flumioxazin (32) is a major compound for weed control in soybean and peanut. Mammals and crops rapidly metabolize 32 by 82-84 85 hydroxylation of the cyclohexene ring and cleavage of the imide linkage. Carfentrazone-ethyl (33), a phenyl triazolinone, is quickly hydrolyzed in plants to the corresponding carboxylic acid which retains much of the protox-inhibitor potency of the parent compound. Rapid metabolism of 33 in soybeans by other pathways contributes to its selective action. Others (Figure 3). Fluroxypyr (34),86-88 a pyridyloxyacetic acid ester, is used to control broad leaf weeds and woody brush. It is an auxin undergoing esterase activation of the 1-methylheptyl ester to the acid. The isoxazole herbicide isoxaflutole (35)89,90 inhibits p-hydroxyphenyl pyruvate dioxygenase (HPPD) which converts p-hydroxyphenyl pyruvate to homogentisate indirectly inhibiting carotenoid biosynthesis. It is bioactivated to a diketonitrile (35A), the actual inhibitor and herbicide. A structurallysimilar HPPD inhibitor, the cyclohexanedione nitisinone, is used as a pharmaceutical to treat hereditary tyrosinemia Type 1. The isoxazolidinone herbicide clomazone (36) 91-93 suppresses the biosynthesis of chlorophyll and other plant pigments at the first committed step of the pyruvate to chloroplastic isoprenoid pathway. This target site-inhibiting block involves clomazone bioactivation to 5hydroxyclomazone and further to 5-ketoclomazone (36A).

PROFUNGICIDES 14α-Demethylase (Figure 4). There are four major triazole fungicides collectively referred to as conazoles that act as sterol demethylation or 14α-demethylase inhibitors. Two have an oxirane ring (epoxiconazole and difenoconazole) and a third a dioxolane ring (propiconazole) which undergo metabolic ring cleavage among other reactions. The fourth is the profungicide triazolinthione prothioconazole (37)94,95 which is oxidatively bioactivated to prothioconazole-desthio (37A) with the essential triazole moiety to serve as a 14α-demethylase inhibitor. Others (Figure 4). Several of the early multisite (multivalent) fungicides have retained their potency remarkably well with little selection of resistant strains of fungi. They are generally converted to products which react with and inactivate the SH groups of amino acids and enzymes of fungal proteins to disrupt 96,97 lipid metabolism, respiration and ATP production. The ethylenebis(dithiocarbamate) mancozeb (38) introduced in 1961 is still the most important compound of this type. Thiophanate-methyl (39)98,99 is metabolically converted to the antitubulin carbendazim (39A). The thiadiazinethione dazomet (40)100 is a metabolic precursor of the biocide methyl isothiocyanate (40A). Fosetyl-aluminum (41)101-103 or aluminum tris-O-ethylphosphonate is metabolized by an undefined hydrolase to phosphorus acid, the



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active agent which inhibits mycelium formation and fungal sporulation and stimulates plant defense mechanisms without oxidation to phosphoric acid. Microbial oxidation of orthophosphite varies

Figure 4. Major profungicides with important sites of metabolism and bioactivation shown by arrows. considerably between microorganisms relative to phosphate formation and utilization for growth,104 perhaps contributing to fungicidal specificity.

PATHS TO SUCCESS The goal of using a prodrug or propesticide is to deliver the active agent to the desired target site at the right time and place, resulting in selective action within or between organisms. The derivatizing group or protective moiety can be introduced prior to application or by the organism. Activation or deprotection is usually achieved by various esterases and CYPs. These enzymes are of multiple types within each organism and the balance varies with the organism. They also vary with previous exposure to other chemicals as individuals (induction and inhibition) or populations (selection for resistance). The potential combinations and complexity of the interactions preclude accurate predictions of optimal substituents for designer compounds. However, it is usually clear which functional groups and substituents are candidates for modification by the chemist and the organisms. Fortunately, target site and organismal sensitivity assays provide guidelines for focusing the optimization process.


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This perspective is based on 100 major drugs and 90 major pesticides selected for their importance (monetary success). About 1 in 5 of these drugs and pesticides are actually prodrugs or propesticides. They have often been optimized twice, first for the molecular target and then for the protective substituent or delivery system. This is a small sample of the perhaps thousands of relevant compounds many of which achieved major importance and scientific understanding but no longer fall in the top monetary category. Prodrugs and propesticides as compounds and principles considered here should be interfaced with the broader picture considered in excellent recent reviews.105-113 Improved prodrugs and propesticides depend on combining the knowledge about the target and compound metabolism. The topic is fascinating, the challenges and rewards are great, and the paths to success are becoming increasingly evident.

AUTHOR INFORMATION Corresponding Author *Address: Department of Environmental Science, Policy & Management UC Berkeley 130 Mulford Hall #3114 Berkeley, CA 94720 Tel: +1-510-642-5424. Email: [email protected] Note The author is not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

ACKNOWLEDGEMENTS We give special thanks to Minhchau (MC) Le Nguyen (B.S. 2017, Department of Nutritional Sciences and Toxicology: Physiology and Metabolism at the University of California, Berkeley) and Ilsa Zhang (B.S. 2017, Department of Nutritional Sciences and Toxicology: Molecular Toxicology at the University of California, Berkeley) who assisted with devotion and distinction in searching, compiling and presenting the information in this Perspective.

ABBREVIATIONS 5-HT, 5-hydroxytryptamine; ACCase, acetyl-CoA carboxylase; ACh, acetylcholine; AChBP, ACh binding protein;



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AChE, acetylcholineesterase AChR, ACh receptor; ADHD, attention deficit hyperactivity disorder; cGMP, cyclic guanosine monophosphate; CYP, cytochrome P450; CYP51, sterol 14α-demethylase; DHPS, dihydropteroate synthase; DMI, demethylation inhibitor; EPSPS and epsps, EPSP synthase; GMO, genetically-modified organism; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; HPPD, p-hydroxyphenyl pyruvate dioxygenase; IMI, imidacloprid; LDL-C, low-density lipoprotein cholesterol; mAChR, muscarinic acetylcholine receptor; nAChR, nicotinic AChR; Neonic, neonicotinoid; NET, noradrenaline transporter; NPC1L1, Nieman Pick C1 like 1; NS5B, nonstructural protein 5B; P2RY12, purinergic receptor P2Y12; PDE5, phosphodiesterase type 5; PEP, phosphoenol pyruvate; PPARα, peroxisome proliferator – activated receptor alpha; PPO, protoporphyrinogen oxidase PRO, prothioconazole;


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S1P, sphingosine-1- phosphate; SNT, serotonin- norepinephrine transporter

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Author Biography John E. Casida obtained his Ph.D. degree in entomology, biochemistry, and plant physiology at the University of Wisconsin, Madison (1954). He was Professor of Entomology at Madison from 1954 to 1963 and Professor of Entomology and Toxicology at Berkeley starting in 1964. He is currently Professor of the Graduate School and holds the Edward A. Dickson Emeriti Professorship. His research emphasizes pesticide chemistry, molecular toxicology, and comparative biochemistry. He is a member of the U.S.


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National Academy of Sciences, the U.K. Royal Society, and the European Academy of Sciences and a recipient of the Wolf Prize in Agriculture.


Why Prodrugs and Propesticides Succeed - Chemical Research in

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