39/40 - Medchem AntiVirals Flashcards
Process of AV Drug Discovery
Acquiring Chemicals
Random Design
Analog Approach
Bio-Structural Approach
Isolation from Natural Sources
Screening
HTS in vitro / Animal Models
Process of AV Drug Discovery
IDENTIFYING LEADS
Structural Modifications
Understanding the
Molecular Mechanism –> Interaction w/ Active Site
OPTIMIZING
lead molecules
Nucleoside Analogs
- *What modification gave GREATER SELECTIVITY** for
- *Viral Thymidine Kinase?**
- OH –> monophosphate
Iodo Group of Idoxuridine
REPLACED by:
-CH2Ch3** or **CH=HBR
Compound has higher affinity for viral thymidine kinase
Nucleoside Analogs
What modification gave
PROTECTION FROM DEACTIVATION?
& by what enzyme?
Iodo Group of Idoxuridine
REPLACED by a:
strong EWG substituent
-F / -CF3 / -NO2
these compounds could
INHIBIT - THYMIDYLATE SYNTHASE
Monophosphate –> INACTIVE form
Nucleoside Analogs
LAMIVUDINE + EMTRICITAMINE
NRTI’s
What improvements were made?
Modification of the SUGAR structure
C-OH –> S
Deoxyribose is replaced by a:
1,3 - oxothiolane** = **NO 3-OH group
VVV
PREVENTS the 5’-3’ phos linkage for DNA chain elongation
CHAIN TERMINATOR OF DNA SYNTHESIS
Nucleoside Analogs
ENTECAVIR
What improvements were made?
Modification of the SUGAR backbone
O -> C=C
Furonose Oxygen** –> **Methylene Group
Creating a Carbocyclic Ring that can
Overcome the degradation problem in normal nucleosides
phosphorolyases would normally CLEAVE the N-glycosidic linage
Entacavir Triphosphate INHIBITS:
HBV Polymerase Activities
Nucleoside Analogs
ACYCLOVIR
Guanine Derivative
- *Inhibition of Viral-coded DNA polymerase:**
- *Removes 2 Carbons** from Sugar Base
- 3-OH is now MISSING* -> addition of other N’s prevented
- *= CHAIN TERMINATION**
More SELECTIVE to Infected cells:
Requires Metabolism –> MONOPhosphate by:
VIRAL Thymidine Kinase
followed by host-cell kinases –> triphosphate for activity
Nucleoside Analogs
Acyclovir + Ganciclovir + Penciclovir
What ESSENTIAL function groups are retained?
Hydroxy-group = “Sugar-Like”
Guanine Nucleoside base
- *Guanine** substituted at:
- *N-9 Position**
Ganciclovir:
extra hydroxymethylene –> CMV infection
1st Prodrug strategy for Nucleoside Analogues
ESTER ANALOGS
MoA / Drugs
- *Ester Analogs** are bioconverted/hydrolyzed by
- *ESTERASES** –> active acid form
Ex:
VALACYCLOVIR = L-valvyl ester prodrug of acyclovir
Valganciclovir = “ of ganciclovir
Famciclovir=DiAcetyl esters, ofpenciclovir
3rd Prodrug Strategy for Nucleoside Analogs
Avoiding the 1st Phosphorylation Step
= Rate-limiting step
Nucleosides have 2 major problems as drugs:
1) NEG CHARGE @phys pH PREVENTS the crossing of biological membranes –> poor ORAL absorption
2) RAPID degradation by PHOSPHOTASES
Prodrug strategy:
1) MASK phosphate group w/ Protecting groups = LIPOPHILIC
2) Removal of protecting group by enzymes –> traps anionic monophosphate INSIDE cell
3) still prodrug –> needs triphosphate to be active
Nucleoside Analogs
ADEFOVIR & TENOFOVIR ALEFENAMIDE/Disoproxil
What 3 IMPROVEMENTS were made?
Nucleoside PHOSPHONATE prodrugs
1st Phosphorylation (rate-limiting step) is BYPASSED
delivered as 5’-monophosphate form
+
Neg Charge of PHOS is MASKED –> ↑Lipophilicity
+
Addition of CARBON b4 Phosphate –> ↑antiviral activity
Neuraminidase Inhibitors
VIRMIDINE (Taribarvirin) –> RIBAVARIN (Tribavirin)
What Improvements were made?
Ribavirin = RBC toxicity
Taribavirin = PRODRUG of Ribavirin
w/ better LIVER-targetting + safety
@physiologic pH:
+pos+ charge from partial protonation of carboximide group
contributes to the relative slowness –> drug cross cell membrane (RBC)
first pass metabolism:
C=O –> C=NH
Drug Targets for Influenza Virus
AMANTADINE + RIMANTADINE
what do they target?
M2 ION CHANNEL
Amantadine + Rimantadine
no longer used due to RESISTANCE
Drug Targets for Influenza Virus
Oseltamivir = Tamiflu
MoA
COMPETITIVE INHIBITOR of:
Viral NEURAMINIDASE
normally removes SIALIC ACID from glycoproteins on the surface of human cells that help new virions EXIT the cell
- *PRODRUG:**
- *hydrolyzed** –> active carboxylic acid derivative
Drug Targets for Influenza Virus
Oseltamivir = Tamiflu
What MAJOR CHEM. MODS were made to make the drug?
SIALIC ACID –> Oseltamivir
Cyclohexene Ring** = **TRANSITION STATE MIMIC
mimics transition state of sialic acid
Sialic Acids: Glycerol Moiety (2x -OH)
- -> 3-Pentyl Ether side chain (2x - CH3)
- *↑LIPOPHILICITY**
_NRTI = Nucleoside Reverse Transcriptase Inhibitors_ **ZIDOVUDINE = AZT**
What improvements were made?
1st HIV approved treatment
THYMIDINE** –> **AZIDO (N=N=N)
OH –> -NNN
targets the catalytic site of HIV RT
- *DNA Synth + Replication is terminated**
- because nucleosides canNOT bind to NITROGEN group of AZT*
_NNRTI = NON-Nucleoside RT inhibitor_ **EFAVIRENZ = EFV**
Modifications
TRIFLUOROMETHYL GROUP
+
CycloPropylAcetylene group
on a:
Benzoxazinone Nucleus
makes A LOT of interactions w/ neighboring contacts
hydrophobic contacts
BioIsosterism Approach** + **SAR modifications
HIV Protease Inhibitors
ATAZANAVIR
Type / Improvements
- *AZA-Dipeptide** = PEPTIDE ANALOG
- *PyridinylPhenyl side chain**
HIV Protease Inhibitors
DARUNAVIR
Improvements / Features
NON-PEPTIDIC protease inhibitor
design based on the:
“BACKBONE BINDING CONCEPT”
Hydrogen Bonds between:
Bis-THF**+**p-aminosulfonamide
in the backbone of the enzyme active site
What are the:
Two structural components are necessary for integrase binding?
Integrase Inhibitors
Elvitegravir / Raltegravir / Dolutegravir
HydroPHOBIC BENZYL moiety
buries the highly hydrophobic pocket near the active site
+
CHELATING TRIAD
that binds the 2 Mg2+ ions in a hydropholic region, anchoring the inhibitor on the protein surface
Mg2+ & Mn2+ are critical cofactors in the integration phase“Strand Transfer Inhibition”
