Proposals for New Antimalaria Drugs - Part 3
This web page is intended to update with several new chemical systems my previous two essays about antimalaria drugs in Part 1 and Part 2 .
Oxazines are heterocyclic compounds including the N-O group as ring atoms . Compounds with 3-6 ring atoms are most common . The following sketch outlines practical synthesis routes to oxazines with 6 , 3 , and 5 ring atoms respectively :
The possibility of forming oxazines with four ring atoms was briefly alluded to in Part 2 , by the photochemical 1,2-cyclization of C-nitrosos (and maybe N-nitrosos as well) with olefins :
A sensitizer might be needed in these cyclizations , as was the case in the photochemical cyclization of electron-rich olefins with triplet oxygen , to form the highly reactive 1,2-dioxetanes (the references are at the end of this web page) . In all these cases the olefin , imine , and nitroso reactants can have many different substituents , thus permitting a "fine-tuning" of the physical , chemical , and pharmacological properties of the oxazine products .
N-Alkoxyamines , R-O-NH2 , were discussed in Part 2 . Compounds in which the N atom of the reactive N-O group is alkylated might also be effective antimalarial agents . Such an approach is outlined in the sketch below :
In the above scheme I have suggested a chemical "trick" to possibly improve the reaction of the alkyl chloride , RCl , with the mildly nucleophilic phenoxide anion . A catalytic quantity of an iodide salt such as NaI , soluble in the polar solvent (acetonitrile) , is included in the reaction mix . The nucleophilic iodide would displace Cl from the RCl to form the transient RI , which is more reactive with phenoxide than RCl .
The redox properties of Methylene Blue , a remarkably potent antimalaria compound , were pointed out in Part 2 . The deep blue cationic dye can oxidize sugars in an alkaline environment (and possibly in a mildly acidic medium as well) by the following mechanism (the "blue bottle experiment") :
Methylene Blue+ Cl- + 2 H+ + 2 e- (ex glucose) ----------> Leucomethylene Blue + HCl
Then : Leucomethylene Blue + HCl + ½ O2 (air) ------------> Methylene Blue+ Cl- + H2O
Net reaction : 2 H+ + 2 e- (ex glucose) + ½ O2 (air) -------------> H2O
Because Methylene Blue can be regenerated from its colourless reduced form (Leucomethylene Blue) by an oxidizer such as atmospheric oxygen , it can act in a catalytic manner to consume glucose and oxygen inside the Plasmodia parasites . However , any compound in general that can act in a similar mildly oxidizing manner , removing (2 H+ + 2 e-) or (H+ + e-) from the organism will deprive it of its glucose food source , if not oxygen . As such , it could be a possible antimalaria drug candidate . Pyrilium salts are of interest in this regard .
The reduction of pyrilium salts in an acidic medium produces a nonionic intermediate which is rapidly hydrolysed to an open chain enedione :
Pyrilium salts are typically prepared by the acid-catalysed dehydration of enediones :
"Under the influence of acids , cis-2-ene-1,5-diones or their enol forms are converted by dehydration back into pyrilium salts . Accordingly , any synthetic method resulting in 1,5-enediones is , in fact , a method for the synthesis of pyrilium salts" (Balaban , Schroth , and Fischer , p. 246) .
Such a dehydration process is unlikely to occur in vivo ; pyrilium cations might nevertheless be able to oxidize glucose and other simple sugars as Methylene Blue does .
A synthesis scheme for preparing pyrilium salts via an enamine and enedione is outlined below :
This multi-step procedure has the advantage of permitting the synthesis of pyrilium salts with a considerable degree of functionalization , which is often an important consideration in the design of a series of pharmacologically-active compounds . Balaban and co-workers have developed a simplified technique of preparing pyrilium salts in a one-pot reaction , in particular those of the 2,4,6-trimethylpyrilium cation . One of their earlier methods is sketched below :
The tert-butyl chloride probably decomposed to isobutylene (providing C4) , which was then acylated twice by the acetyl chloride ; this intermediate was dehydrohalogenated to the enedione , which dehydrated and cyclized to the pyrilium salt . After workup ,
"The aqueous solution contains 2,4,6-trimethylpyrilium chloroaluminate ....... from which various salts may be prepared" (Balaban and Nenitzescu , p. 3557) .
Several detailed preparations of 2,4,6-trimethylpyrilium salts (perchlorate , tetrafluoroborate , and triflate) have been published in Organic Syntheses , as well as a procedure for the 2,4,6-triphenyl analogue . A relatively simple and easy preparation of 2,4,6-triphenylpyrillium tetrafluoroborate in 34% yield , suitable for organic chemistry students , is described in the web page , "Preparation of ET(33) : A Solvatochromatic Dye", by Professor Douglass F. Taber of the University of Delaware . Note that the perchlorate salts , while valuable as reactive intermediates , are dangerously explosive (pressure sensitive) . The BF4- and triflate salts are chemically stable , but seem unsuitable for use in potential drug compounds . Salts with the stable hexafluorophosphate anion , PF6- , might be more acceptable for use as medications in humans (I believe a fluorophosphate compound has been used as an anticaries agent in toothpaste) . PF6- anions are furnished by the corresponding acid HPF6 (commercially available as 60% aqueous solutions) , as shown in the following sketch :
The 2- , 4- , and 6-carbons in the pyrilium ring are electrophilic centres , and react readily even with medium-strength nucleophiles . Substitution by alkyl and aryl groups at these positions sterically hinders nucleophilic attack on them , and helps to stabilize the pyrilium ring . Inert or non-nucleophilic spectator anions , such as BF4- , PF6- , ClO4- , and triflate are often used with the pyrilium cations to improve the long-term stability of the salts . However , a simple halide anion like chloride can accompany a pyrilium cation . The anthocyanins are brightly-coloured naturally occurring plant dyes that have a pyrilium salt component . They are glycosides , consisting of a sugar (or sugars) , combined with an aglycon (an anthocyanidin) . This latter molecule is a phenolic pyrilium chloride salt , an example of which is malvidin :
One day last Fall (of 2007) , I noticed big splotches of bird "poop" on my car . They were a deep bluish purple colour , almost as dark as printer's ink when I wiped the mess off onto a damp absorbent paper towel . I was mystified as to the nature of the purple dye , until several weeks later I noticed the same coloured bird mess on a nearby sidewalk which was overhung with tree branches . Peering into the branches I discovered a bird's nest , and wrapped around many of the branches I noticed a grape vine , to which were still attached many clusters of small wild grapes . The anthocyanin malvin is found in grapes , giving them their red to purple colour . Evidently the birds were consuming the wild grapes , and malvidin was being excreted unchanged from them . Bird "poop" - guano - is known to be strongly alkaline (one of its components is the alkaline guanidine) , and malvidin in a basic medium is blue , and possibly even purple . Lacking any experimental evidence to the contrary , I'm speculating that the anthocyanidin malvidin , a naturally-occurring pyrilium salt , is the source of the deep bluish-purple guano I observed (and cleaned off my car) .
The naturally-occurring anthocyanidins such as malvidin are said to be very unstable :
anthocyanins normally exist as glycosides ; the aglycone
component alone is
extremely unstable" (International Programme on Chemical Safety bulletin) .
Like Vial's bis-quats (see in Part 1) , they are poorly absorbed into the body through the intestinal wall . They can also be degraded by intestinal bacteria :
"Studies in rats have shown that some anthocyanins (notably pelargonidin , delphinidin , and malvidin) were subject to degradation by intestinal bacteria" (IPCS bulletin) .
These problems might be at least partially resolved by the design and synthesis of small , stable pyrilium molecules , with steric protection provided at the 2- , 4- , and 6-carbons in the ring . The objective would be to develop a pyrilium compound as chemically and physiologically stable , and as effective against Plasmodia as Methylene Blue , but lacking its dye properties ; i.e. , be either colourless in solution , or very light-coloured . For example , the compound 2,4,6-trimethylpyrilium hexafluorophosphate could be prepared by a variation of the published synthesis of the BF4- analogue , substituting HPF6 for the HBF4 in the procedure . Such a salt would be soluble in water and reasonably stable as an aqueous solution , making it feasible for testing against Plasmodia cultures in vitro .
An aminium cation is similar to a molecule of a tertiary amine , except that one of the electrons from the lone pair on the nitrogen has been removed , making the compound a radical cation (accompanied by a spectator anion , of course , derived from the oxidizing agent that removed the electron) . Aminium cations substituted with aromatic groups are generally fairly stable , and can be isolated as deep blue crystalline compounds . Aminium cations derived from aliphatic compounds are very unstable , and have been studied as reaction intermediates . The perchlorate salt of 1,4-bis(dimethylamino)benzene is commonly called "Wurster's Blue", after its German chemist discoveror . The radical cation is stabilized by p electron resonance in this and other aromatic-substituted aminium salts :
Aminium radical cations are oxidizing agents ; for example , the interesting Wurster blue compound tris(4-bromophenyl)aminium hexachloroantimonate has been used to catalyse the Diels-Alder reactions of relatively unreactive dienophiles with dienes . It abstracts a p electron from the dienophile , greatly increasing its electrophilicity - and reactivity . Reduction of an aminium salt regenerates the corresponding tertiary amine :
Wurster Blue compounds can be readily prepared by the addition of one equivalent of an oxidizer to an equivalent of a tertiary aromatic amine , preferably in solution . Halogens can be used as the oxidizer :
deBoer et al. comment ,
"The iodide was preferred above the corresponding chloride and bromide , as the latter compounds are unstable" (p. 542) .
Possibly in the chloride and bromide cases halogenation of the aromatic ring by the more reactive halogen might have occurred . Perchlorate was the inert , non-nucleophilic spectator anion in the original Wurster Blue compound , but the deBoer group found that it was randomly distributed in the crystalline solid , making their X-ray diffraction analysis difficult . The Wurster Blue salts are readily soluble in water . A video demonstration of the formation of the deep blue aminium radical cation by the oxidation of 1,4-bis(dimethylamino)benzene in bromine water , with photos and a discussion , is provided on Peter Keusch's web page , "Wurster's Blue".
As with the pyrilium salts above , the PF6- salt of the simple 1,4-bis(dimethylamino)benzene aminium cation might be the best candidate compound to investigate for possible antimalarial activity :
The redox half-reaction indicates that acidic hydrogen peroxide is a powerful oxidizer ; combined with HPF6 it should be able to form the aminium PF6- salt easily , cleanly , and in high yield .
Quinones are well-known in organic chemistry and electrochemistry as oxidizers , being easily reduced to the corresponding hydroquinones :
Quinone + 2 H+ + 2 e- ---------------> Hydroquinone
Three representative quinones are sketched below :
Generally , the addition of electron-withdrawing substiuents (eg. halogens , CN) increases the reduction potential of the quinone , i.e. makes them more strongly oxidizing . Conversely , the addition of electron-donating substituents such as alkyl groups makes them weaker oxidizers with respect to the unsubstituted p-benzoquinone .
Hydroquinone can be bis-methylolated at C2 and C5 , as in the nice example below :
Similarly , it might be possible to substitute an alcohol for the sec-amine (dimethylamine) in the above reaction :
Oxidation of the hydroquinone to the quinone using sodium chlorate is a simple , high-yield method that was originally used to prepare p-benzoquinone . It seems to be generally applicable to hydroquinones . p-Benzoquinone ("quinone") is fairly toxic and an irritant ; the Merck Index gives its LD50 as 130 mg/kg (rats , orally) . The addition of electron-donating alkyl substiuents at C2 and C5 will hopefully reduce its toxicity while still retaining its critical oxidizing property .
I've indicated throughout these three web pages on antimalaria drugs the possible use of ethyl carbitol as a "tail" or side chain in many of the compounds . This is intended to illustrate the attachment of a partly hydrophilic , partly lipophilic substituent to the drug candidate molecule . Such a "tail" may be necessary in the cases of the peroxide and N-O compounds , which have protective hydrophobic "heads" around the reactive O-O and N-O groups . The tails may assist in the solubilzation or dispersion of the drug molecules in blood . Ethyl carbitol may or may not be effective in this objective . Vennerstrom and co-workers have studied a wide range of organic peroxides as antimalaria drugs , and their findings suggest that the more water-soluble compounds are less effective against Plasmodia :
be cheap and effective this drug would have to be a pill . A pill
that dissolves in water and is absorbed by the stomach . But OZ 3
was an oil that did not dissolve in water . The solution should
have been simple .Vennerstrom redesigned the molecule adding
chemicals that made it dissolve in water , but this wasn't the
answer (Bill Paterson , narrator ; BBC Radio interview with J. L. Vennerstrom and others) .
Prof. Jonathan Vennerstrom : Although we had achieved better water solubility we had lost the antimalarial activity . So we had to keep going back to the drawing board time and time again before we really worked this out .
Narrator : Vennerstrom was caught in a trap . Every time he tried to make the molecule dissolve in water it lost its antimalarial properties . And every molecule which killed malaria didn't dissolve in water.
So ethyl carbitol tails may make their attached molecules too water-soluble , hence ineffective against Plasmodia . Of course , such alcohol-derived tails could be "fine-tuned" , with three , two , one , or zero oxygen atoms (in the last case , by using fatty alcohols such as octyl , decyl , and lauryl alcohols ; but then the drug candidates might be too lipophilic) . My objectives in suggesting ethyl carbitol as a tail were simplicity , economy , chemical inertness , and hopefully effectiveness . If the latter property is unrealized , the researcher would then have to look elsewhere for a suitable polar tail for the peroxide and N-O compounds ; and they almost certainly will require such a tail . The small , compact oxidizing molecules like Methylene Blue apparently don't need a tail ; the entire molecule , which is fairly water-soluble , is the complete "poison package" that kills the malaria parasite .
Halogen-Oxygen Organic Compounds
The rationale for studying 1,2-oxazines and other such N-O compounds as possible antimalaria drugs was that the bond dissociation energy of the N-O bond (35.8 kcal/mol) was roughly comparable to that of the peroxide O-O bond (33.2 kcal/mol) , making N-O compounds almost as reactive as peroxides . Let's compare the dissociation energies of other covalent oxide bonds :
These figures suggest that molecules with S-O and P-O single bonds might also be interesting to examine in our search for new antimalaria drug candidates . We could conceive of molecules such as RxOSRy and RxOPRyRz , but they are still in uncharted territory right now . Sulfate and orthophosphate are rather innocuous anions , so they must also be ruled out in this study .
The halogen-oxygen bonds are even weaker than O-O , N-O , S-O , and P-O single bonds ; organic compounds with halogen-oxygen combinations might thus be promising candidates for our consideration . We'll focus on organic molecules with I-O bonds , as they are reasonably stable under ambient conditions and so might be studied as possible drug compounds .
Iodine-oxygen organic compounds are strong oxidizers . Both iodosobenzene (Ph-I=O) and iodoxybenzene (PhIO2) will explode when heated (at 210 ºC and 230 ºC , respectively) . Iodosobenzene diacetate (m.p. 158-159 ºC , dec.) is more stable . It has an unusual T-shaped structure :
In the above molecular model , the red sphere represents the iodine(III) atom having a trigonal bipyramid coordination ; the blue spheres are the acetates (OAc) , and the two small gray spheres are the iodine electron lone pairs . Since the iodine has a total of ten valence shell electrons in this compound instead of the usual octet , it's called "hypervalent iodine". The organic chemistry of hypervalent iodine has been studied extensively in the past couple of decades , as I-O organic compounds have been found to be useful oxidizing reagents . Several textbooks and reviews are available on the subject .
The following scheme outlines how iodoxybenzene with a carbityl tail at C4 might be prepared :
Several techniques for alkylating phenols , using various bases , are described in the literature . Here's a suggestion using triethylamine as the basic reagent :
A catalytic quantity of an iodide , such as NaI , is included in the mix to accelerate the reaction of RCl with the phenoxide anion . If this technique is successful , a synthesis scheme for the preparation of the intermediate 4-carbityl-iodobenzene could be based on it :
4-Iodophenol is commercially available (eg. Aldrich Chemicals) , and can be prepared by published procedures (eg. Organic Syntheses) . I included the suggested method shown in the above sketch as an interesting experiment . Hydrogen peroxide instantly oxidizes iodide to iodine , which should then iodinate the reactive phenol in the para position . Since iodine is a relatively expensive element in all its forms , the objective here would be to consume it quantitatively in the production of the desired product and not waste any of it in by-products .
In Part 2 I discussed the possibility of preparing a new type of peroxide , an a-cyanoperoxide . Because iodide anion is as strong a nucleophile as cyanide , the same sort of reaction with iodide and peroxides might provide the analogous a-iodoperoxide (which isn't an I-O compound , but it's convenient to discuss it in this section) :
Since hydrogen peroxide oxidizes iodide to iodine , the intermediate organic peroxide-tertiary alcohol must be prepared first in a reasonably pure form . In the model compound case , the bis-cyclohexyl intermediate is well-known , being manufactured in large quantities (presumably) as a Nylon 6 polymer precursor (this process was sketched in Part 2) . Then , in an acid medium the nucleophilic iodide will displace the protonated hydroxyls and - hopefully - produce the a-iodoperoxide .
Splitting of the peroxide bond of the a-iodoperoxide by the heme's iron(II) should regenerate the original ketone component and release iodine free radicals (i.e. zerovalent iodine atoms) into Plasmodia's interior . Elemental iodine is well-known , even to the general public , as a broad-spectrum disinfectant ("tincture of iodine", still sold in pharmacies) :
The use of elemental iodine as an antiseptic dates back to 1839 ........ The combination of iodine with various soluble polymers led to a class of new compositions known as iodophores ....... The complexes function by rapidly liberating free iodine in water solutions . They exhibit good activity against bacteria , molds , yeasts , protozoa , and many viruses (Trotz and Pitts , p. 232) .
If they can be synthesized and are reasonably stable , a-iodoperoxides might be considered as a new and potentially very powerful type of iodophore , and could be highly effective against Plasmodia and other types of protozoa and microparasites in general .
Another type of halogen-oxygen compounds , the organic hypochlorites , might be evaluated for antimalarial activity . Tert-butyl hypochlorite is readily prepared from the reaction of t-butyl alcohol and acidified sodium hypochlorite . It's thermally stable at room temperature , but is light-sensitive . Higher molecular weight analogues might be more stable , in particular if the O-Cl "head" is sterically protected by alkyl or aryl groups :
The simple oxyhalogen anions might also be very interesting to evaluate as antimalarial agents . Iodates and periodates are used as oxidizing reagents in organic chemistry . Perchlorate is also a well-known oxidizer (and can sometimes form explosive combinations with organic compounds) . As mentioned above in the quinone section , sodium chlorate is an equally strong oxidizer :
ClO3- + 6 H+ + 6 e- -------------> Cl- + 3 H2O E0red = 1.451 V
Sodium chlorate is an important industrial chemical which is mainly used as a powerful bleaching agent in the pulp and paper industry ; minor uses include herbicides and matches . Chlorate is manufactured by the anodic oxidation , in electrochemical cells , of the chloride anion :
NaCl + 3 H2O + electricity --------------> NaClO3 + 3 H2 (g)
As such it's an inexpensive bulk chemical shipped in railway tankers . Actually , there's a chlorate electrochemical plant , Eka Chimie , located in Magog , Quebec , Canada , not far from my home . It's powered by hydroelectricity from the Magog River which flows by the plant site :
In water solutions sodium chlorate exhibits oxidizing properties only when combined with an acid , which converts it to the highly unstable chloric acid , HClO3 :
"Chlorates in neutral and alkaline solutions at room temperature do not show oxidizing properties . In acid solution chlorates are a source of chloric acid" (Clapper , p. 634) .
The actual bleaching agent generated in situ in wood pulp bleaching is chlorine dioxide , produced by the decomposition of the chloric acid intermediate :
ClO3- + Cl- + 2 H+ ------------> ½ Cl2 + ClO2 + H2O
The above reaction occurs when hydrochloric acid is used as the acidifying agent in the mix (Clapper , p. 641) . Sulfuric acid is also used in sodium chlorate pulp bleaching to generate the superpowerful oxidizer ClO2 in the process . The pH inside Plasmodia's food vacuole is thought to be mildly acidic (about 5.2) , so the entry of chlorate anion into the parasite and its decomposition to the ferocious chlorine dioxide should result in the organism's destruction . By the same token , any sodium chlorate medication would have to be shielded , by an enteric coating , from the hydrochloric acid gastric juices in the stomach . Such a coated tablet or caplet would dissolve in the mildly alkaline environment of the intestine (drug delivery by means of a suppository would be less desirable , I think , especially with children) .
According to the Merck Index (14th edition , 2006 , p. 1481) , the LD50 (rats) of NaClO3 = 12,000 mg/kg , which is a fairly low toxicity . A study in 1948 demonstrated the relatively low toxicity of sodium chlorate to laboratory rats (7-8 g/kg) and sheep . A detailed medical report was published in 2006 describing how a man who attempted to commit suicide by swallowing herbicide containing the equivalent of 27g of NaClO3 (!) was revived by an ER team . Although in severe distress initially , his "...... renal function returned to normal along with the hemoglobin levels , two months after intoxication" (Ranghino et al. , p. 2972) . Sodium chlorate definitely isn't an acute poison such as sodium cyanide ; rather , I'd say it's moderately toxic and its ingestion by an adult in a single dose of any more than a gram or two should be avoided . Even that dose should have an enteric coating to protect it against reactive stomach acid .
The Wikipedia article on sodium chlorate states ,
"Due to its oxidative nature , it [sodium chlorate] can be very toxic if ingested . The oxidative effect on hemoglobin leads to methemoglobin formation , which is followed by denaturation of the globin protein and a cross-linking of erythrocyte membrane proteins with resultant damage to the membrane enzymes . This leads to increased permeability of the membrane , and severe hemolysis . The denaturation of hemoglobin overwhelms the capacity of the G6PD enzymatic pathway - in addition , this enzyme is directly denatured by chlorate , reducing its activity . Therapy with ascorbic acid and Methylene Blue may be effective , however ; since Methylene Blue requires the presence of NADPH that requires normal functioning of G6PD system , it is less effective than in other conditions characterized by hemoglobin oxidation . Acute severe hemolysis results, with multi-organ failure , including DIC and renal failure".
Although this description sounds alarming , there is almost always a trade-off in drug therapy of the effective dose (to destroy the parasite or otherwise cure the patient) versus the toxic dose (where harm is caused to the patient by the ingested chemical) . Of course , it's always desirable to optimize the former quantity and minimize the latter . What these values might be for the possible application of sodium chlorate in the treatment of malaria in humans would have to be determined clinically . In the end , sodium chlorate might prove to have an acceptable efficacy against Plasmodia and at the same time exhibit minimal toxic side-effects at those dosage levels .
It's interesting to note that NaClO3 causes methemoglobin formation in blood . Methemoglobin is , in effect , "rusted-out hemoglobin" ; that is , the iron(II) atoms in the hemoglobin have been oxidized by the chlorate to iron(III) . Methemoglobin's Fe(III) is incapable of forming a coordinate covalent bond to an oxygen molecule , although it can bond weakly to a water molecule . Recall that rust is hydrated iron(III) oxide . If chlorate can rust out normal , healthy human blood , it should similarly be able to oxidize the waste heme produced by Plasmodia feeding on the hemoglobin . Such oxidized heme , which is thought to be a reaction product of heme with the peroxide antimalaria drugs , is unable to crystallize to hemozoin , and so builds up in the parasite and eventually kills it .
Because sodium chlorate is a cheap industrial chemical , it couldn't be patented as an antimalaria drug , which would make it uninteresting to drug companies . If it proved to be effective against Plasmodia , perhaps a "generic drug" manufacturer could produce the medication on demand for government aid agencies , which would distribute it for free or at low cost in the field .
The possibility of a simple anion like chlorate being an effective antiprotozoal agent shouldn't be ignored or overlooked . I'm reminded of another such common compound , dichloroacetate anion , which is currently being investigated as an antineoplastic drug (against cancer tumours) . Good fortune often favours an open (and well-informed) mind !
1,2-dioxetanes : S. Mazur and C.S. Foote , "Chemistry of Singlet Oxygen . IX . A Stable Dioxetane from Photoxygenation of Tetramethoxyethylene", J. Amer. Chem. Soc. 92 (10) , pp. 3225-3226 (1970) .
Balaban , Schroth , and Fischer : A.T. Balaban , W, Schroth , and G. Fischer , "Pyrilium Salts", Adv. Heterocyclic Chem. 10 , pp. 241-326 , A.R. Katritzky and A.J. Boulton (eds.) , Academic Press , New York , 1969 .
Balaban and Nenitzescu : A.T. Balaban and C.D. Nenitzescu , "Pyrilium Salts Obtained by Diacylation of Olefins . Part II . The Two Pyrilium Salts Formed in Diacetylation of 2-Methylbut-2-ene", J. Chem. Soc. 1961 , pp. 3553-3561 .
aliphatic : Y.L. Chow et al. , "Nonaromatic Aminium Radicals", Chem. Rev. 78 (3) , pp. 243-274 (1978) .
deBoer et al. : J.L. deBoer , A. Vos , and K. Huml , "The Crystal and Molecular Structure of N,N,N',N'-Tetramethyl-p-diaminobenzene Iodide (Wurster's Blue Iodide)", Acta. Cryst. B24 (4) , pp. 542-549 (1968) .
Vennerstrom : Y. Tang , Y. Dong , and J.L. Vennerstrom , "Synthetic Peroxides as Antimalarials", Med. Res. Rev. 24 (4) , pp. 425-448 (2004) . "........ within a given peroxide chemical family , the more lipophilic members are more potent and possess better oral antimalarial activity in animal models than their more polar counterparts" (p. 441) .
reviews : P.J. Stang and V.V. Zhdankin , "Organic Polyvalent Iodine Compounds", Chem. Rev. 96 (3) , pp. 1123-1178 (1996) . "....... the chemical properties and reactivity [as oxidizers] of iodine(III) species are similar to those of Hg(II) , Tl(III) , and Pb(IV) , but without the toxic and environmental problems of these heavy metal congeners ......" (p. 1124) . "Iodosylbenzene is an effective oxidizing reagent ; however , its insolubility due to its polymeric structure significantly restricts its practical usefulness" (p. 1126) . This is why I selected iodoxybenzene as the template for modification as a drug candidate compound . V.V. Zhdankin and P.J. Stang , "Recent Developments in the Chemistry of Polyvalent Iodine Compounds", Chem. Rev. 102 (7) , pp. 2523-2584 (2002) .
Trotz and Pitts : S.I. Trotz and J.L. Pitts , "Industrial Antimicrobial Agents", vol. 13 , pp. 223-253 , Kirk-Othmer Encyclopedia of Chemical Technology , third ed. , M. Grayson and D. Eckroth (eds.) , John Wiley , New York (1981) .
Clapper : T.W. Clapper , "Chloric Acid and Chlorates", vol. 5 , pp. 633-645 , Kirk-Othmer Encyclopedia of Chemical Technology , third ed. , M. Grayson and D. Eckroth (eds.) , John Wiley , New York (1979) .
about 5.2 : J. L. Vennerstrom , "Amine Peroxides as Potential Antimalarials", J. Med. Chem. 32 (1) , pp. 64-67 (1989) ; p. 66 .
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