medicinal chemistry of antiparasitic drugs (2)
TRANSCRIPT
Medicinal Chemistry of Antiparasitic Drugs (2)
Sherif Elshahawi, PhD
9401-297U
Source: Foye's Principles of Medicinal Chemistry, 8th edition, 2019
Learning Objectives§ To identify the chemical structures of the main antiparasitic agents and drug classes
§ To understand the basic medicinal chemistry and structure-activity relationships of the antiparasitic agents.
§ To describe the metabolism of antiparasitic drugs in the body
§ To describe the mechanisms of action of the antiparasitic agents to enhance desired properties and decrease adverse effects.
§ To evaluate the important toxicities associated with the antiparasitic agents.
Antimalarial DrugsClassification
Class I: 4-substituted quinolines
Class II: Phenanthranemethanol
N
HO
Cl
Cl
FFF
halofantrine
HO
Class III: 8-aminoquinolines
N
X
NNH2
N
O
HON
H
H
QuinineNCl
HNN
ChloroquineNCl
HN N OH
Hydroxychloroquine
HOHN
N
FFF
FF
F
mefloquine
H
N
pamaquine
O
NHN
N
tafenoquine
O
NHH2N
O
O
FFF
Class IV: aminopyrimidinesN
NH2
N
N
NH2
N
NH2
Cl
pyrimethamineO
NH2
OO SHN N
N
O
sulfadoxine
NHO
Cl
Cl
Cl
lumefantrine
N
OH
HN
Cl Namodiaquine
N
O
NHH2N
primaquine
Antimalarial DrugsClassification
Class V: NaphtoquinoneO
O
OH
Cl
O
Oatovaquone
Class VI: BiguanidesH2N N
HNH2
NH NH
Class VII: Artemisinins
H
HO O
H O
O
O
artemisinin
H
HO O
H O
O
OOH
O
O
artesunate
H
HO O
H O
O
O
artemether
H
HO O
H O
O
O
arteether/ artemotil
H
HO O
H O
OH
O
dihydroartemisinin
O
OO F F
F
FF F
arteflene
O
O O1,2,4-trioxane
O O
1,2-dioxane
Class VIII: Antibiotics
O
HNN
O
S
OH
HO
HO
Cl
H
clindamycin (Cleocin)
OH
NH2
OOOHOOH
H OHH
N
OH
doxycycline (vibramycin)O
OO
O
HO
O
O
OHO
N
HO
N
OHHO
azithromycin (Zithromax, Zmax)
Cl
NH
NH
NH
NH NH
proguanil
Antimalarial Drugs
§ The two drugs together (Malarone) exhibit synergy in which proguanil reduces the effective concentration of atovaquone needed to damage the mitochondrial membrane
§ Used against Plasmodium, Toxoplasma gondii, and Pneumocystis carinii
Class V. Napthoquinone Class VI. BiguanidesH2N N
HNH2
NH NHO
O
§ Selectively inhibits the parasitic cytochrome bc1 interfering with the electron transport chain and the mitochondrial membrane potential
§ Not used alone: high lipophilicity results in slow uptake and prolonged exposure to the parasite leading to high natural frequency of mutation and thus resistance.
§ Take with food to enhance bioavailability
§ Proguanil as an antifolate is active in the cytosol
§ The active form of proguanil is cycloguanil, which acts as a DHFR inhibitor.
§ Considered a prodrug
OH
Cl
O
Oatovaquone
Cl
NH
NH
NH
NH NH
proguanil
Cl
NH
NH
NH
NH NH
proguanil
Cl NN
NNH2
H2N
cycloguanil
Antimalarial Drugs
§ The plant Artemisia annua has been used in Chinese traditional medicine to treat fever 2,000 years ago and to treat malaria since 1596.
§ In 1972, Tu Youyou isolated and characterized the active ingredient (artemisinin)
§ She was awarded half the Noble prize in Physiology/ Medicine in 2015 for this discovery
Class VII. Artemisinins
H
HO O
H O
O
O
artemisininArtemisia annua
Antimalarial Drugs
§ The artemisinin derivatives have an endoperoxide bridge. Artemisinins are built on the unstable 1,2,4-trioxanes or 1,2-dioxane ring system
§ Heme iron in parasite bind and cleave the endoperoxide bridge of artemisinins leading to the generation of highly reactive free radicals which damages parasite membrane by covalently binding to membrane proteins
Class VII. Artemisinins O
O O1,2,4-trioxane
O O
1,2-dioxaneH
O OO
H
HO O
H O
O
O
artemisinin
H
HO O
H O
O
OOH
O
O
artesunate
H
HO O
H O
O
O
artemether
H
HO O
H O
O
O
arteether/ artemotil
H
HO O
H O
OH
O
dihydroartemisinin
Antimalarial Drugs
§ The artemisinins are hydrophobic in nature with the exception of artesunate, which is available as a water-soluble hemisuccinate salt
§ Less frequent resistance
§ Food increases absorption
§ Artemisinin-based combination therapy (ACT), to provide resistance and synergism show high cure rates..
§ artemether–lumefantrine (Coartem)
§ amodiaquine–artesunate (Camoquin)
§ chloroquine–artemisinin (ASAQ-Winthrop)
§ artesunate–sulfadoxine–pyrimethamine
Class VII. Artemisinins
H
HO O
H O
O
OOH
O
O
artesunate
HO O
O
Antimalarial DrugsClass VIII. Antibiotics
O
OO
O
HO
O
O
OHO
N
HO
N
OHHO
azithromycin (Zithromax, Zmax)
O
HNN
O
S
OH
HO
HO
Cl
H
clindamycin (Cleocin)
OH
NH2
OOOHOOH
H OHH
N
OH
doxycycline (vibramycin)
§ They interfere with protein synthesis.
§ They can be used alone as prophylaxis or in combination with quinine or artesunate as treatment measures.
§ Antibacterial and antiprotozoal drugs.
§ Effective against pneumocystic pneumonia and the extrapulmonary disease.
Sulfamethoxazole (SMX)–Trimethoprim (TMP)(Co-trimoxazole, Bactrim, Septra, Cotrim)N
N NH2
NH2O
OO
trimethoprim
NO
HN
SO
ONH2
sulfamethaxazole
O OH
NH
O
NH
NO
HN
H2N N NH
O
OH
dihydrofolic acid
O OH
NH
O
NH
HN
O
HN
H2N N NH
O
OH
tetrahydrofolic acid
DNARNA
PuriesPyrimidines
DHFR
O
H2N
OH
PABA
OPPN
O
HN
H2N N N+
DHS
dihydropteridine analogX X
N
NH2N
NH2O
OO
trimethoprim
NO
NHS
O
O
H2Nsulfamethaxazole
Anti-Pneumocystis and Antitrypanosomal Drugs
§ Has pentyl and amidine groups
§ It selectively binds AT rich region of the parasite DNA through hydrogen-bonding with the amidine proton § It also inhibits the mitochondrial topoisomerase in P. jirovecii, which leads to double-strand cleavage and
linearization of the circular mitochondrial DNA.§ Carrier proteins are used for cell transport. Thus, resistance arises from down-regulation of these carrier proteins
genes
§ Available as the water-soluble isethionate salt, which is used both IV and as an aerosol. Poorly absorbed through GI
Pentamidine Isethionate (Pentam 300, Nebupent)
NH2
NH
OO
H2N
NH
OHSO
HO Opentamidine isethionate
pentylamidine
amidine
Anti-Pneumocystis and Antitrypanosomal Drugs
§ A derivative of methotrexate (both are folate antagonist)
§ Methotrexate (cancer chemotherapy) has a polar glutamate side chain, is transported into human cell via a carrier-mediated transport system
§ The glutamate moiety in trimetrexate is replaced with a lipophilic moiety and is thus absorbed by the cell via a passive diffusion.
§ Trimetrexate inhibits DHFR. It binds to P. jirovecii DHFR a few hundred times stronger than trimethoprim and a few times than methotrexate.
Trimetrexate Glucuronate (Neutrexin)
N
NH2N
HN
H2N
O
O
O
trimetrexate
O
OH
OH
OH
COOH
OH
glucuronate
pentamidine isethionate
NNN
H2NN
NH2
NO
HN
OHO
OHO
methotrexate
Anti-Pneumocystis and Antitrypanosomal Drugs
§ The “tritryps:
§ Trypanosoma brucei: African trypanosomiasis (African sleeping sickness)
§ Trypanosoma cruzi: Chagas disease
§ Leishmania major: leishmaniasis
NH2
NH
OO
H2N
NH
OHSO
HO Opentamidine isethionate
HN
ONH
O
NHO
HN
O
HNSOH
OO
SHO
O
O SOH
O O
O
NH
SHO
O
OS OHO
O
S OH
O
O
Na
suramin sodium
H2N
N
H2NN
NH
AsS
OH
S
N
melarsoprol
Anti-Pneumocystis and Antitrypanosomal Drugs
§ For African sleeping sickness and river blindness
§ The bis-hexasulfonatednaphthylurea increases the polarity of the compound, and thus does not cross the BBB making it unsuccessful for the treatment of CNS infections
§ The high polarity makes it water-soluble that is poorly absorbed via oral administration and must be IV administered.
§ It inhibits DHFR, a crucial enzyme in nucleic acid synthesis.
§ It inhibits glycolytic enzymes to block energy sources of the pathogen.
Suramin Sodium
Anti-Pneumocystis and Antitrypanosomal Drugs
HN
ONH
O
NHO
HN
O
HNSOH
OO
SHO
O
O SOH
O O
O
NH
SHO
O
OS OHO
O
S OH
O
O
Na
suramin sodium
§ For treatment of trypanosomiasis.
§ Trivalent arsenic reacts with sulfhydryl-containing proteins:
1) pyruvate kinase leading to inhibition of glycolysis and subsequently loss of motility and cell lysis
2) trypanothione reductase
§ Drug of choice for the treatment of late-stage meningoencephalitic trypanosomiasis.
Melarsoprol
H2N
N
H2NN
NH
AsS
OH
S
N
melarsoprol
Anti-Pneumocystis and Antitrypanosomal Drugs
H2N
N
H2NN
NH
AsS
OH
S
N
melarsoprol
NNHN
H2N
N
H2NAs
O
melarsen oxide
proteinHS
HS
OH
HS
H2N
N
H2NN
NH
AsS
protein
S
N
protein
§ Helminths are biologically diverse parasites. They differ in size, life cycle, site of infection and susceptibility to drugs.
S
HN
NHN
OO
albendazole
N
S
N
HN
thiabendazole
HN
NHN
OO
mebendazole
O
O
NN
O
praziquantel
NHHO
HNN+-O
O
oxamniquine
O
O
HO
O
O
HO
HO
OO
O
H
O
O
OH
HOH
ivermectin
N
O
NN
OH
O
OH
O OHO
HO
diethylcarbamazine citrate
Antihelmintic Drugs
OO
O
O
H
OH
H
H
OH
N
O
H
moxidectin
O
Antihelminthic Drugs
N
HN
benzimidazole
12
345
67Benzimidazole
Bioorganic & Medicinal Chemistry Letters 23 (2013) 4221–4224
§ Albendazole, mebendazole, and thiabendazole. They are broad-spectrum with activity against GI helminths.
§ Have poor water solubility leading to low GI absorption (a fatty meal will increase absorption). This is beneficial, as it allows benzimidazoles to treat intestinal helminths.
§ Bind to the protein tubulin leading to inhibition of the tubulin polymerization to microtubules . Thus, microtubulin continues to dissociate from the opposite end, with a net loss of microtubule length.
§ They are selective to the parasite microtubules with minimal host toxicity.
N
HN
benzimidazole
12
345
67
S
HN
NHN
OO
albendazole
N
S
N
HN
thiabendazole
HN
NHN
OO
mebendazole
O
Benzimidazoles
Antihelmintic Drugs
§ Derived from avermectins. Avermectins are natural products isolated in 1978 from soil bacteria§ Satoshi Ōmura and William C. Campbell were awarded the other half of the 2015 Nobel Prize in Physiology/Medicine
discovering avermectins§ Activity against a variety of microfalaria and nematode infection. § Present as a mixture of two avermectins derivatives§ Is a 16-membered macrocyclic lactone connected to 2 sugars§ Take on empty stomach
Antihelmintic DrugsIvermectin (Stromectol)
O
O
HO
O
O
HO
HO
OO
O
H
O
O
OH
HOH
ivermectin
Streptomyces avermitilis
§ It is a γ-aminobutyric acid (GABA) agonist. It causes the affinity to GABA to increase in special receptors at synapses causing an interruption of nerve impulses, leading to possible paralysis or death
§ It binds irreversibly to the glutamate-gated chloride channel
Ivermectin (Stromectol)
The Journal od Biological Chemistry Vol.287, No .48, pp.40232–40238, 2012http://www.jackieheda.com/ngg_tag/ivermectin/#gallery/ivermectin/541
Antihelmintic Drugs
§ For treatment of schistosomiasis and liver flukes (trematode and cestode infections). No activity against nematodes.
§ Take with food
§ Proposed mechanism of Action:
§ It increases the permeability of the worm cells towards calcium causing contraction followed by dislodge
§ Interferes with the adenosine uptake
Praziquantel (Biltricide)
O
NN
O
praziquantel
HN
isoquinoline
Antihelmintic Drugs
§ Tetrahydroquinoline
§ Targets Schistosoma mansoni native to Brazil.
Oxamniquine (Mansil, Vansil)HN
quinoline
oxamniquine
NH
OH
HN
N+O-O
oxamniquine
NH
CH2
OH
HN
N+O-O
metabolic inactivation
NH
COOH
HN
N+O-O
HOOC
CH2
OH
HN
N+O-O
Antihelmintic Drugs
§ The drug is activated and esterified (to the phosphate or sulfate ester) in the organism. The ester dissociates to an electrophile (carrying positive charge). This electrophile alkylates the helminth DNA, interfering with its nucleic acid metabolism.
§ Resistant helminths do not activate oxamniquine.
Oxamniquine (Mansil, Vansil)
oxamniquine
NH
CH2
OH
HN
N+O-O
metabolic activation
NH
CH2
O
HN
N+O-O
SO3H
NH
CH2
O
HN
N+O-O
PO3H2
NH
CH2
HN
N+O-O
NH
CH2
HN
N+O-O
DNA
NH
CH2
HN
N+O-O
DNA
Antihelmintic Drugs
§ DEC is a filaricidal agent, piperazine is more active against nematodes
§ Although chemically similar, the activity against helminths is quite different. Piperazine is active against nematodes, whereas DEC is active against falaria and microfalaria.
§ Proposed mechanism of action is inhibition of microtubule polymerization and interference with arachidonic acid metabolism
Antihelminthic DrugsDiethylcarbamazine (Hetrazan, DEC)
N
O
NN
diethylcarbamazine
piperazine
NHHN
OH
O
OH
O OHO
HO
piperazine citrate
N
O
NN
OH
O
OH
O OHO
HO
diethylcarbamazine citrate
Moxidectin (Cyndectin)
Antihelmintic Drugs
OO
O
O
H
OH
H
H
OH
N
O
H
moxidectin
O
OO
O
O
H
OH
H
H
OH
OH
O
H
nemadectin
§ For the treatment of acute Chagas disease but not effective for the chronic stages of the disease.
§ Nitroaryl compounds for the treatment of trypanosomiasis.
§ Nifurtimox is thought to undergo reduction followed by oxidation and, in the process, generate ROS, such as the superoxide radical anion, hydrogen peroxide, and hydroxyl radical.
§ These species are potent oxidants, producing oxidative stress that can produce damage to DNA and lipids that can affect cellular membranes.
§ Take with food. Alcohol can increase AE
Nifurtimox (Lampit)ON NO
ON S
OO
nifurtoimox
Anti-Pneumocystis and Antitrypanosomal Drugs
§ For treatment of Chagas disease. It is administered orally in a tablet form andavailable only in South American countries.
§ It has a nitroimidazole structure
§ Similar to nifurtimox, it is ineffective during the chronic stage of the disease.
§ Does not catalyze the formation of ROS (unlike nifurtimox). It undergoes a one-electron transfer to the nitro group, which in turn give back the nitroimidazole and a nitrosoimidazole.
§ Nitrosoimidazole can then undergo an electrophilic addition to trypanothione (an essential enzyme system in T. cruzi), leading to its depletion.
Benznidazole (Rochagan)N
NH
O
N+
N
O O-
benznidazole
NO2Re
NO2R
NO2R22H+
R NO2 R NO H2O+ +
Anti-Pneumocystis and Antitrypanosomal Drugs
§ Metronidazole, tinidazole, nitazoxanide and diloxanide furoate are used in the treatment of amebiasis, giardiasis, and trichomoniasis. They all contain heterocyclic rings
§ The nitro groups in metronidazole and tinidazaole generate ROSs that involve oxygen and hydrogen peroxide radicals leading to the DNA cleavage
§ Antimalarial drugs could be classified chemically into eight classes: 4-substituted quinolines, phenanthrenemethanol, 8-aminoquinolines, aminopyrimidines, napthoquinones, biguanides, artemisinins and antibiotics
§ DHS and DHFR are possible antiprotozoal targets
§ Pentamidine disrupts the AT interaction of nucleic acid
§ Trimetrexate glucuronate inhibit DHFR
§ Other anti-pneumocystis and antitrypanosomal drugs include suramin sodium, benznidazole and melarsoprol(arsenic compound)
§ Bezimidazoles are important antihelmintic drugs. They prevent tubulin polymerization
Conclusion
§ Rapid metabolism of the antimalarials by resistant strains of plasmodium Cytochrome P450.
N
O
HON
H
H OH
OHN
O
HON
H
H
Quinine
ONH
NS
OO
N+O
nitazoxanide (NTZ)
O
O O
OH
HO
OH
HOOC
ONH
NS
O
N+O
O
execretion via glucuridation
N
O
Cl
Cl
O
diloxanide furoate
O
O
O
OH
HO
OH
HOOCN
O
Cl
Cl
O
execretion via glucuridation
N
HO
Cl
Cl
FFF
halofantrine
NH
HO
Cl
Cl
FFF
desbutylhalofantrine
Cyp3A4N-dealkylation
Cyp3A4
oxamniquine
NH
CH2
OH
HN
N+O-O
metabolic inactivation
NH
COOH
HN
N+O-O
HOOC
CH2
OH
HN
N+O-O