►
From YouTube: Open Source Antibiotics Science Update Sept 11 2020
Description
Weekly open project meeting for Open Source Antibiotics Series 2.
Full Project: https://github.com/opensourceantibiotics/Series-2-Diarylimidazoles
Relevant GitHub Issue: https://github.com/opensourceantibiotics/Series-2-Diarylimidazoles/issues/26
On the call: Professor Matthew Todd, Dr Dana Klug, Dr Edwin Tse (all University College London), Dr Chris Swain (Cambridge MedChem Consulting), Dr Alvaro Lorente (University of Edinburgh), Dr Ben Perry (DNDi).
A
All
right
welcome
everybody,
open
source
antibiotics
series,
2
meeting
on
friday
september,
the
11th
and
let
me
share
screens
so
that
we
know
what
it
is
we're
looking
at.
A
Hopefully,
that
is
clear
and
everyone
can
see
the
screen.
A
Okay.
So
thanks
for
coming
along
the
the
big
news
you
know
this
week
is
that
we
had
some
compass
tested.
So
I
guess
the
main
thing
I
want
to
do
is
to
have
a
quick
chat
about
future
design
just
before
we
get
to
that.
A
If
I'll
just
highlight
a
couple
of
things,
so
we've
been
having
a
few
conversations
offline
with
various
people
about
what
they're
doing
in
the
project
main
one
is
that
lee
graves
at
the
university
of
north
carolina
chapel
hill,
who
had
agreed
to
do
the
mechanism
of
action
experiments.
A
We
had
a
chat
with
him
and
resolved
what
needs
to
be
done
and
that's
going
to
go
ahead.
I
think
next
week,
caro
wells,
who
has
the
original
compounds,
has
the
two
compounds
that
are
needed
there,
which
which
are
which
I
guess
we're
trying
to
be
consistent
about.
You
know
the
actors
and
inactives
that
we're
using
for
the
project
to
make
sure
that
when
we
publish
it,
we've
kind
of
you
know
got
data
on
the
same
compounds
which
makes
a
simpler
story.
A
C
C
A
Yeah,
it's
a
good
one,
I'll
chase
cara
on
that,
just
to
be
sure
if
the
solas,
maybe
you
could
check
the
nmr
there.
I
think
the
lab
that's
providing
the
mrsa
is
nearby
to
lee,
so
they
could
have
a
quick
test
of
the
compounds
versus
the
organism:
yeah,
yeah,
okay,
good
good
reminder.
Thank
you
important.
A
I
guess
I
was
pleased
by
the
way
to
see
that
these
two
compounds
still
were
active
and
inactive
in
the
latest
results
that
we
just
got
so
there's
a
confirmation,
nothing
needed
on
the
clearance
essays
which
are
happening
in
monash.
Hopefully
we'll
get
this
back
pretty
soon
and
on
some
of
these
other
things,
there
have
been
some
conversations
between
me
and.
D
A
The
company
and
between
me
and
jim
callahan
at
gsk-
and
I
just
can't
quite
report
yet
about
those
agreements,
but
certainly
interesting
conversations
which
are
going
places
about
trying
to
isolate
some
metabolites
and
trying
to
learn
what
we
can
about
what
was
done
in
gsk
on
this
series
back
in
the
day.
A
So
I
will
update
as
soon
as
I'm
able
to
say
things,
and
I
just
got
to
clear
it
with
them
about
what
I
can
say,
but
there's
progress
being
made
at
least
and
just
on
point
seven
they're
still
trying
to
track
down
the
original
report
from
coad
on
these
compounds
from
I'm
guessing
I'm
guessing
that
bill
has
that.
A
So
we
got
a
report
about
how
the
compounds
were
tested,
but
not
the
specific
data
on
these
compounds
and
one
of
the
reasons
why
I'm
interested
is
because
I
guess
I
kind
of
assumed
that
the
original
hit
was
found
by
coad.
But
the
all
of
the
compounds
which
were
screened
was
it
25
or
so
compounds
have
been
screened
elsewhere.
But
but
I
guess
we
were
thinking
that
maybe
they
were
all
screened
by
coat,
in
which
case
there's
a
big
document.
A
I'm
also
assuming
that
that
document
contains
the
information
that
we
have
about
their
toxicity
or
not
versus
you
know
mammalian
cells
which
I'll
come
to
in
a
second.
But
we
need
that
because
we
need
to
be
sure.
A
All
right,
so
the
the
I
mean,
the
main
thing
really
is
the
data
from
the
latest
round
of
screening,
so
paul
stapleton,
my
colleague
here
at
school
of
pharmacy
screened
these
nine
compounds
which
dana
and
ed
had
made-
and
this
is
some
of
these
are
repeats.
Some
of
them
are
to
be
compared
against
the
known
sar
which
we
originally
had,
which
is
on
the
wiki
page.
So
there's
some
of
them
repeats.
Some
of
them
are
new,
so
I
guess
there's
two
sets
of
data
here
which
we
need
to
combine
together.
A
So
the
original
active
was
this
guy
hq2
and
the
originally
inactive
was
the
sky
2
0,
which
is
a
very
small
change,
but
makes
a
big
difference,
and
then
several
of
you,
these
other
ones,
were
synthesized
to
explore
various
aspects
of
things.
This
compound
this
eight
one
two
is
the
one
that
was
so.
This
is
kind
of
the
base
compound
which
everything
is
a
derivative
of,
but
we
realized
we
didn't
actually
have
any
data
on
this
combat,
so
we've
we've
remade
it
and
and
found
that
it
in
itself
is
also
inactive.
A
And
then
these
are
the
other
new
compounds,
including
the
one
that
had
made
with
the
fennel
there,
which
obliterates
the
activity.
So
that's
an
important
data
point
obviously,
and
then
there
are
some
other
ones
here
that
have
been
made,
which
are
all
inactive.
Apart
from
these
with
a
sniff
of
activity,
when
we
have
the
sulfur
there
just
quickly
on
the
point
that
was
made
by
ben
overnight
about
toxicity,
which
is
an
interesting
point,
so
he
was
saying
that
he
is
worried
that
the
chelation
possibility
between
the
red
and
the
green.
E
A
As
a
metal,
collater
would
make
these
compounds
generically
toxic
and
chris,
you
made
the
point
that
well.
Why
doesn't
that
happen?
Why,
then,
or
not
all
these
compounds
active,
which
is
a
good
point
and-
and
I
just
dug
up
the
relevant
bit
of
text
from
the
I
need
to
refresh
those
from
the
from
the
grant
proposal.
A
The
original
grant
proposal,
which
I
I
need-
maybe
danny,
could
check
at
some
point
if
this
is
on
the
wiki,
because
I
couldn't
find
it,
but
I
found
it
the
original
grant
proposal
which
says
this.
So
this
is
the
the
preliminary
data
we
used
to
get
the
grant
going
in
the
first
place.
A
So
all
15
of
these
compounds
that
were
shown,
I
think
in
the
wiki-
were
evaluated
for
cytotox
all
damage
to
similar
sizes
like
this
in
293,
where
the
concentration
of
devices
two
for
within
two-fold
of
twelve
micrograms
per
mil
four
compounds
concentration
at
ten
percent.
Hemolytic
activity
in
hemorrhoidal
cells
was
greater
than
32
micrograms
per
mil,
so
there's
a
window
of
therapeutic
activity.
So
there
is
some
toxicity:
there's
a
window
therapy
therapeutic
activity,
but
again
it
would
be
nice
to
see
to
check
whether
that
correlates
with
the
activity
against
mercer
in
the
first
place.
A
So
yeah
so
ben
has
also
said
a
couple
of
other
things
here
about
the
need,
perhaps
to
do
an
analog
sweep
of
the
green
ring.
Now
he
was
originally
suggesting
that
we
go
from
a
two-paradile
to
three
and
four,
and
that
has
already
been
done.
So
we
we
know
from
the
original
data
that
the
three
and
the
four
isomers
are
inactive.
A
But
as
far
as
I
can
tell,
those
are
the
only
analogs
we
have,
we
haven't
done
anything
else
at
that
position.
As
far
as
I
know
in
the
green
position,
apart
from
now
trying
the
fennel,
so
I
think
that's
the
limit
and
ben
was
suggesting
other
heterocycles
there,
like,
I
think
he
said
three
pyrozole
or
four
imidazole.
A
I
think,
is
that
what
he
was
saying
so
you're
suggesting
you
try
to
mess
around
with
that
position
a
little
bit,
and
I
guess
it
depends
if,
if
we
can
generate
those
compounds,
so
he
was
saying
replacing
two
peridol
with
other
things
was
a
way
of
getting
their
clearance
down,
which
is
another
one
of
the
things
we're
trying
to
do
in
this
project.
A
A
E
C
A
Yeah
we
got
that
current
report
right
about
the
same
time
that
paul
was
starting
his
essay,
I
mean
literally
the
same
kind
of
hour,
so
we
weren't
able
to
change
it.
But
we
need
to
look
at
the
the
incubation
time,
for
example,
and
check
whether
it's.
D
Well,
would
it
wouldn't
the
the
bead
pull
down
the
protein
target
searching
if
this
thing
was
metal
binding?
Wouldn't
it
cause
a
bunch
of
protein
targets
to
pop
up
on
the
screen,
so
we
would
kind
of
know
that
way.
If
this
thing
was
metal,
binding.
A
I
don't
know,
I
think
I
think
seeing
a
correlation
with
generic
toxicity
would
be
a
bad,
a
bad
thing.
I
mean,
I
think,
that
that
would
be
a
roadblock
right
there.
A
A
So
I
think
you
know
keeping
the
heteroatom.
There
may
be
a
wise
thing
to
do,
given
what
we
found
with
the
three
and
the
four
pyridines
being
inactive.
Maybe
that's
what
we
need
to
do,
but
I
think
this
raises
enough
of
an
issue
that
we
need
to
keep
an
eye
on
the
toxic
screening,
just
parenthetically
about
that.
A
Getting
very
close
now
to
be
able
to
do
some
of
this
talk
screening
quickly
here
in
the
school
of
pharmacy,
just
one
last
little
paperwork
thing
to
to
get
sorted
out,
and
then
we
may
be
able
to
do
that
here
quickly.
So
maybe
we'll
have
the
answer
more
quickly
than
we
than
we
think,
but
I'm
hoping
it's
in
the
card
report
because
they
should
do
that
by
default.
A
Also,
I
mean
just
on
the.
Let
me
just
take
a
step
back
here,
looking
at
any
compounds
with
activity,
so
these
guys,
with,
of
course,
our
original
hit
and
and
the
sulfurs
up
here
and
from
the
original
sar
the
compounds
that
have
activity
here
again
with
the
sulfur
here
again
with
the
sulfur.
I
guess
we
have
some
oxygens
down
here,
but
the
compounds
with
the
activity
appear
to
have
sulfurs,
and
I
don't
know
what
to
make
of
that
or
whether
that
is
remotely
significant.
A
D
A
D
So
you
could
make
a
you
could
probably
get
the
a22
yeah
the
immersive
make
the
one
with
the
four
four
microgram
molar
four
microgram
millimeter.
Rather
you
can
get
the
cell
phone
of
that.
A
Yeah
I
mean-
I
think
ed
will
talk
about
this
in
a
minute
because
he's
going
after
some
of
the
oxidized
compounds
of
one
of
the
aims
of
the
interaction
we're
trying
to
generate
with
the
company
haifa
is
to
show
that
we're
getting
oxidation
and
try
to
fish
out
some
of
those
oxidized
species.
And
that's
that's
the
whole
point.
A
So
again,
I
guess
so.
Some
of
the
data
from
monash
may
also
show
that
there
could
be
a
correlation
between
propensity
to
be
oxidized
and
potency.
I
guess
that's
also
something
we're
trying
to
look
for,
but
it's
a
good
point
I'll
check
in
with
paul
about
paul
stapleton,
about
the
nature
of
the
answer.
A
Okay,
I
mean
I
might
at
this
point
so
one
of
the
other
things
that
that
ben
says
is
which,
in
this
in
this
post,
which
is
very
useful,
is
that
they
do
have
some
some
compounds
that
may
be
relevant
to
us,
and
I
guess
I
need
to
follow
up
with
him
about
this.
Some
information
about
molecules
that
may
that
they've
made
on
a
related
project
that
they
may
be
able
to
share
with
us.
A
So
that's
that's
something
I'll
be
chasing
up
with
him,
always
nice
to
be
able
to
use
compounds
that
have
been
made
already
all
right.
Ed!
Are
you,
okay
to
talk
a
little
bit
about
chemistry,
ongoing
and
maybe
a
little
bit
about
design
on
the
basis
of
these
data.
E
E
Okay,
yeah
so
I'll
just
go
over
dana's
stuff
as
well
thanks,
so
she's
been
working
on
these
kind
of
couplings,
so
she's
tried
to
use
some
different
suzuki
conditions
with
this
oxazole,
which
wasn't
working
with
the
initial
conditions,
but
it
seems
that
it's
just
giving
deburbinated
material
and
then
she's
also
been
working
on
these
emitters.
Oil
compounds
and
trying
to
do
suzuki's
on
them.
So
for
this
trittle
one
she's
getting
decomposition,
and
strangely
for
this
methyl
emitterzole,
she
managed
to
get
this
dimer.
D
E
I
guess
there's
a
transfer
of
the
borrowing
I
don't
know,
but
she
was
thinking
of
switching
the
coupling
partners
so
having
like
this
as
the
rna
and
that
as
the
bromine
instead
and
seeing
if
that
helps
so
yeah
we've
purchased
that
bromo
and
we'll
see.
If
that
works.
E
A
D
A
Okay,
I
mean
obviously
these
compounds
because
we
we
need
to
try
and
make
them.
Obviously
these
are
based
on
the
same
kind
of
core
right
yeah
to
to
peridot,
which
is
fine,
because
we
should
finish
what
we
start.
E
E
I
was
hoping
that
maybe
dana's
suzuki
conditions
would
have
worked
because
I've
got
the
cell
phone
veronica,
which
I
could
couple
but
yeah,
I'm
not
too
sure
about
that
at
the
moment,
maybe
going
to
microwaves
might
help
but
yeah
and
in
the
meantime
I've
also
been
making
more
of
the
core.
So
I've
been
scaling
up
progressively
each
time
and
so
for
this
last
time
I've
kind
of
deliberately
extracted
the
aqueous.
Even
though
it's
like
a
lot
of
dmf,
but
that
seems
to
have
like
improved
the
yield.
E
Almost
double
you
just
have
to
deal
with
getting
rid
of
all
that
dmf,
which
can
be
a
bit
of
a
hass
tool.
But
I
guess
getting
more
is
worth
it
and
then
yeah
as
ben
was
suggesting.
So
these
kind
of
pyrazole
and
imidazole
compounds.
E
So
I
had
a
quick
look
at
the
respective
starting
materials.
So
I
guess
we
would
need
like
this
alpha
bromo
ketone
of
these
and
yeah
they're,
not
really
that
easy
to
get
to.
So
I
don't
know.
Maybe
there
are
some
alternative
isomers
of
this
that
are
easier,
but
I'll
be
a
little
concerned
about
this
too
yeah.
A
The
implication
from
ben's
message
is
that
they've
made
compounds
like
this,
so
you
might
want
to
reach
out
to
him
and
say:
do
you
have
any
synthetic
stuff
you
could
share
with
us.
A
A
So
to
find
out
who
you
know,
who's
put
things
in
that
position
and
what's
available.
That
would
be
neat
in
terms
of
doing
an
analog
sweep
on
the
south
west,
but
maintaining
the
imidazole
for
now
and
maintaining
there
being
something
the
carbon
based
on
one
of
the
nitrogen.
So
try
and
keep
it.
A
Fuzzy
yeah-
and
I
mean
at
the
moment
you
know,
keeping
the
benzothiaphine
in
the
in
the
northwest
seems
like
a
sensible
thing
to
do
based
on
potency,
but
not
if
it's
a
not
ultimately.
If
it's,
if
it's
a
liability,
we
don't
know
it's
a
liability.
Yet,
but
at
least
we're
getting
program
compounds.
B
I
guess
the
other
compound
that
would
be
interesting
to
make
is
the
replace
the
pyridine
with
the
pyrimidine.
A
E
A
I
had
a
feeling
we
mentioned
that
compound
before,
but
that's
absolutely
right.
Yeah.
D
I
believe
the
one
that
was
mentioned
was
the
one
that
was
from
acetyl
pyrazine,
which
is
a
perfume
ingredient.
A
E
It's
pretty
messy
to
be
honest,
like
after
the
column,
the
column
itself
is
pretty
stained.
I'm
sure
probably
alvarez
also
encountered
this
when
he
made
them,
but
yeah.
C
D
B
B
D
You
said
that
the
column
was
stained
afterwards
to
me.
That
almost
makes
me
think
of
like
oxidation
products.
Is
this
done
in
vacuole,
the
bringing
of
the
acyl
bromide
and
the
amine
together.
E
I
mean
yeah,
it's
just
you
know
under
room
temperature,
I'm
sorry,
80
degree
conditions,
it's
nothing
sealed
yeah!
It's
just
to
air.
D
A
A
I
think
that's,
probably
that's
probably
everything
that
we
were
gonna.
We
were
gonna.
Do
oh
yeah,
I
mean
the
one
last.
I
think
I
guess
dana's
on
the
on
the
train
or
something
at
the
moment.
There
was
a
this
issue
to
do
with
just
the
the
impurity
that
we
saw
or
the
signal
that
we
saw
in
the
in
the
nmr
last
time
that
daniel
was
seeing
in
some
of
these
nmrs.
That
was
a
mobile
hydrogen
bonding
type
signal.
E
A
A
A
The
most
obvious
thing
would
be
a
chelated
h,
but
then
you've
got
a
salt,
which
is
fine,
but
we
should
know
if
it's
the
salt
from
them
from
the
mass
back.
A
A
A
A
F
Hi
matt,
this
is
ben
hi.
I've
just
managed
to
dial
in
about
three
minutes
ago.
Sorry,
so
I
I
cuz,
I
saw
that
I
thought
there
were
a
couple
of
comments
about
the
comment
that
I
left
at
random
this
morning.
So
I
just
want
to
know
if
there's
anything
that
I
can
help
with
on
that
side,.
A
A
There
was,
though,
this
very
I'll
just
go
to
the
relevant
thing
here,
so
you
were
saying
if
you
can
see
the
screen
about
the
analog
sweep
of
the
green
ring
here,
which
is
a
great
idea.
We've
already
got
data
on
the
four
and
five
items.
Sorry,
these
three
and
four
isomers,
which
are
inactive.
So
that's
been
done
already,
but
we.
A
So
we
haven't
played
with
that
position,
and
ed
was
just
talking
about
the
synthesis
of
with,
with
maybe
other
coordinating
heterocycles
in
that
position,
and
we
were
hoping
that
maybe
you'd
already
made
some
of
these
things
and
had
a
decent
way
of
making
those
compounds.
F
E
F
Okay,
so
all
of
our
compounds
would
have
been
almost
all
of
our
compounds
of
that
type,
usually
with
substituents
on
the
fennel
on
the
six-membered
ring.
You
know
methyls
and
chlorides
and
whole
bunch
of
methoxys,
and
things
like
that.
We've
also
got
a
couple
examples
of
the
one
the
next
one
over,
which
is
the
saturated
version.
Five
secs.
We
don't
have
any
examples
of
five
five.
You
know
semi-saturated
like
your,
which
seems
to
be
where
you're
coming
from,
and
the
other
thing
is
that
most
of
ours
are
at
the
three
positions.
F
The
way
you
have
your
methylenedioxy
fennel
ring
in
your
hip
compound.
We
have
a
an
amino
linker
to
the
nitrogen
between
the
aromatic
ring
and
the
heterocycle
or
an
oxygen.
F
Of
steps
away,
but
we've
made
a
lot
of
these
sorts
of
compounds
and
there
are
a
few
that
may
be
a
little
bit
closer
to
the
sort
of
things
you
want
to
test.
That's
why
what
I
was
offering
is
to
go
through
that
set
and
maybe
pull
you
know.
10
representative,
diverse
examples
out
and
send
them
on
to
you
that.
F
I
mean
some
of
them,
some
of
them.
We
have
the
ring
fence
because
they're
tied
up
in
you
know
they're
encumbered
because
of
where
they've
come
from,
but
I'm
pretty
certain
that
at
least
half
of
them
are
we're
free
to
do
whatever,
whatever
we
want
with
and
have
samples
so.
B
F
I
saw
an
example
that
had
been
known
that
I've
been
put
forward.
I
think
correct
me
if
I'm
wrong,
but
I
think
anthony
put
forward
a
version
where,
instead
of
a
female
ring
at
that
position,
it
was
a
morphaling.
We
definitely
have
that
compound
and
it
was
interesting,
but
it
was
just
a
heads
up
because
you
know
we
were
we
were.
F
All
of
a
sudden,
you
know
the
toxicity
on
the
cell
line
was
the
same
as
it
was
against
the
parasites,
but
the
things
I
would
point
out
that
you
should
probably
check.
I
would
take
you
know
the
exact
compound
you've
got
here.
What
is
that?
Oh,
eight,
six,
eight
and
swap
out
the
pyradil,
the
two
paradigm.
F
Maybe,
and
then
the
other
thing
to
check
is
that
you
can
get
rid
of
the
paradigm
and
replace
it
with
an
electron,
rich
phenyl
in
our
series,
so,
for
example,
a
dimethoxyphenyl
or
a
para
dimethyl
amino
aniline,
which
okay,
yes,
it's
an
angling
but
from
an
sar
perspective
could
be
interesting
and
it
was
those
sorts
of
things
where
you
make
the
elect.
Make
the
the
fennel
ring
a
little
bit
electron
rich.
That
seem
to
also
work.
A
Interesting
just
to
clarify
on
this
guy
here,
eight
one:
four,
this
compound
has
in
the
in
the
northwest
this
blue
portion.
F
F
Yeah
and
of
course,
you
know
the
obvious
thing
I
should
point
out
there
is
that
that
ring,
particularly
when
you
have
an
aromatic
ring
at
the
two
position,
I
mean
that's
a
massively
privileged
structure.
There
are.
There
are
launch
drugs
with
that,
like
with
zolpidem
a
lot
of
the
sort
of
zebra.
A
lot
of
the
z
drugs
for
insomnia
are
exactly
that
cool.
F
So
there's
a
lot
of
stuff
out
there,
except
section
so
yeah
I'll
I'll,
see
what
I
can
pull
together.
That
is
on
income.
But
how
much
do
you
need
to
test.
F
A
F
F
A
F
Yeah
and
what
we
can
do,
I'm
going
to
suggest
10
or
so
in
the
first
instance,
just
to
get
a
diversity
scan
across
our
sar
and
then,
if
we
see
hits,
we
can
obviously
dive
deeper.
A
Yeah,
that's
amazing,
and
if
there
was
chemistry
done
by
somebody
to
vary
that
ring
on
the
imidazole,
if
if
there
was
a
good
disconnection
or
a
good
approach
for
that,
that
would
be
great
to
know.
Because
ed
and
dana
would
like
to
look
at
that.
F
Okay,
so
when
you
have
when
you're
making
compounds
like
eight
one,
four
that's
made
through
a
one,
that's
made
for
a
one
part:
multi-component
reaction,
where
you
condense,
an
amino
pyridine,
an
aldehyde
and
a
tosmic
reagent,
a
nice
nitrile.
Sorry,
another
nice
nitrile
analysis,
cyanide,
yeah,
nice,
nitrogen
same
thing
yeah,
so
the
chemistry
is
a
little
bit
capricious
because
the
iso
cyanide
can
be
either
sometimes
be
so
reactive.
You
can't
do
anything
with
it
and
other
times
it
can
be
so
stable
that
it
doesn't
react.
F
F
F
That
chemistry,
yeah
yeah
yeah
totally
so
we're
actually
still
working
on
that
series
for
one
of
the
two
parasites
and
that's
being
done
by
lori
ferenz,
oh
really,
who
you
know
so
they're
making
compounds
like
that.
We
made
a
ton
of
these
components
of
wushi
yeah.
F
That
makes
it
easier
okay,
so
we
yeah
and
the
you
know
the
stuff,
the
stuff
that
laurie's
doing
that's
under
an
nih
grant,
in
which
it's
been
very
clearly
specified
that
there'll
be
no
pattern
sort
so
which
I
don't
think,
there's
any
reason
why
those
would
be
encumbered
and
we
should
be
able
to
share
with
those
those
would
be
relatively
easily
awesome.
That's
great.
F
Japan
from
a
cruisy
english
mania
variously
colonia,
so
did
we
test
it
against
manure?
Phantom,
I
mean
we
were
able
to
get
compounds
that
were
really
pretty
potent
against
tropes
on
the
cruise
and
have
decent
pharmacokinetics,
and
then
they
didn't
work
in
vego.
F
So
now
we're
just
looking
at
it
for
leash,
which
is
a
little
trickier.
It's
difficult
to
get
the
potency
down
unleash
sufficiently
and
we've
not
been
able
to
get
a
compound
that
has
any
kind
of
exposure
and
still
has
activity
against
leaf.
B
B
F
So
I
mean
we've
been
working
on
this
off
and
on
and
off
for
about
three
or
four
years
so
yeah
it.
It
doesn't
ring
a
bell,
but
I
can
go
and
check
okay,
it.
It's
a
weird
one
right,
just
my
gut
feel
there
is
that
that
is
not
a
particularly
aminable
coupling
position,
and
I
don't
know
I
mean
that's
like
completely
gut-
feel
right,
it's
one
of
those
ones
where
you
look
at
and
go.
F
B
F
Oh
yeah,
absolutely
but
yeah,
but
I
mean
you
know.
I
think
at
first
glance.
That's
where
you,
where
one
would
focus
the
efforts
right,
but
I'm
just
in
our
experience,
weirdly
that
two
that
two
paradile
seemed
to
be
the
point
at
which
you
know
when
we
finally
changed
that
that
was
when
we
lost
we
had
all
of
our
worries
disappeared
in
terms
of
mouse
microphone,
stability
and
election
stability.
F
And
we
had,
I
mean
unsubstituted
or
methylated
versions
of
the
core,
so
eight
one
four
like
where
it's
either
you
know
unsubstituted
or
just
methyl
groups
on
that
six
membered
ring
which
again
you'd
think
that's
a
metabolic
hot
spot.
But
when
you
swap
the
two
position
out
for
a
an
nh
containing
five
members
wing
imidazole
pyrozole
there,
you
know
the
metabolic
stability
was
right
down
and
we
got
good
decay.
B
F
We
made
a
bunch
of
we're,
not
pyrimidine
pyridoxine.
Definitely
it
lost
a
bit
of
potency
so
whether
we
generated
metabolic
stability
data.
F
At
that
point
I
don't
know
because
right
now
we
get
mets
dab
on
all
compounds
that
are
made
because
they
said
you
know
gifting,
that
to
northeastern,
but
when,
when
north
eastern
weren't
making
the
compounds
which
is
about
half
of
the
data
set,
if
not
more
it
wasn't
we
weren't
getting
that
box
stability
data
on
everything
we
were
already
getting
on
potent
compounds,
so
I
I
again
I
have
to
go
and
check
so
I'm
on
my
phone,
so
I
don't
have
the
full
date
set
in
front
of
me.
F
Mean
I
have
a
manuscript
that
is
finalized
and
I'm
just
waiting
for
approval
from
the
from
various
partners
to
to
publish
it,
so
that
will
be
in
primark
I've
seen
for
about
half
the
series
that
might
answer
some
of
the
questions
and
there's
full
experimental.
You
know
there's
a
200
page
experimental
in
there.
A
I
guess
a
target
becomes
this
814
compound
with
the
benzothiaphine
absolutely
yeah
to
check
that
so
yeah,
ed
and
dana.
That
I
think,
is
going
to
be
unfortunate.
F
F
Think
it
was
palladium
or
platinum,
but
against
a
while
ago
it
wasn't
active.
So
we
never
fold
it
up
for
us.
F
F
Yeah
or
I'll
send
it
on
to
you,
I
mean
I've
got
it.
Was
we
worked
on
this
open
synthesis
network
for
a
while,
with
some
people
at
imperial
there's
a
master
student
imperial?
We
made
a
bunch
of
compounds
on
this,
so
yeah
I've
got
I've
got
experimentals.
I
just
need
to
get
my
laptop
and
and
then
I
can
see
and
make
sure
that
I
can
upload
them.
F
Yeah
I
mean
making
compounds
exactly
like
the
you
know,
the
ones
that
you
have
so
the
eight
six
eight
type
where
it's
our
two
and
arrow
at
the
three
with
the
saturated
five-membered
five-membered.
I
don't
have
any
suggestions
on
that
because,
as
I
said,
everything
comes
to
this
three
component,
but
three
and
three
this
the
three
three
reagent
mcr,
gives
you.
The
eight
gives
you
the
five
six
to
get
a
five
five.
You
don't
get
it.
E
F
So
I
don't
have
much
I
can
import
on
that,
I'm
afraid
yeah.
A
F
That's
that
one
I
did
pick
up
on
and
that's
when
I
went
back
and
tried
to
dig
out
the
previous
okay,
all
right
thanks
and
the
other
thing
I
would
definitely
suggest
on
this.
If
you
can
is
you
know,
chin
is
trying
to
trying
to
get
an
sp3
center
in
here
somewhere
either
at
the
three.
Ideally
at
the
three
position
I
mean
you've
got
some
in
the
ring
system,
which
it's
not
too
bad,
but
just
it's
a
bit
flat
at
the
moment.
Isn't
it
it'll.
F
To
see
I
joined
just
as
you
were
talking
about
the
n
oxide,
I
think
as
a
byproduct,
but
obviously
that's
going
to
twist
the
plane
a
little
bit
and
so
you're
going
to
end
up
with.
That
could
be
an
interesting
compound
to
check
and
also,
if
that
that
should
tell
you
a
little
bit
about
the
metal
collision.
If
that's
active,
then
it
doesn't
calculate.
D
F
F
These
versions-
I
don't
know
in
hours
we
have
the
nh
in
between
the
ring,
the
two
yeah
at
the
three
position,
and
so
you
kind
of
have
an
additional
hydrogen
bond.
That's
gonna
maybe
make
it
plain.
Modeling.
F
F
If
anything
else,
crop
supper
comes
to
mind
I'll,
let
you
know
but,
like
I
said,
like
I
said
in
my
message,
the
first
time
I
saw
these
was
today
when
I
popped
up
on
a
twitter
feed,
and
I
was
like,
oh
okay.
So
that's
why
I
dived
in
and
said
that
we
were
able
to
do
something
it
makes
twitter
worthwhile.
Doesn't
it
well
because
yeah
it's
good
for
being
distracted
for
getting
depressed
and
now
obviously
for
helping
out
with
science?
So
let's
go
yeah.
F
And
because
the
open
source,
antibiotics,
you
know
of
all
the
os
projects
that
matt
is
involved
with
it's
the
one
that
I
have
the
least
exposure
too,
so
I
jump
on
it
every
now
and
then
so
that's
why
I
hadn't
followed
up
on
this.
Okay.
F
Yeah
chemistry-wise:
these
are
nice
molecules
right
and,
and
it's
coolly
able
to
get
make
these
six
for
these
five
fives,
because
five
fives
I
mean
five
five
rings
are
cool
and
it'll,
be
I
don't
know
what
the
simplicity
is
of
making
that
ring
you're
making
it
from
the.
If
I
remember
correctly,
it
was
a.
F
B
F
F
Imagine,
oh
I'll
have
to
go
and
check
I'm
not
promising
anything,
but
I
think
now
I'm
just
thinking
about
it.
The
one
thing
we
might
have
is
where
you
have
that
five-membered
saturated
ring,
I
think
we
might
have
the
six-membered
ring
saturated
with
an
oxygen
in
it,
so
kind
of
like
the
morphaline
imidazole
as
a
fused
core,
which
is
a
really
cool
molecule,
so
yeah,
basically
818,
but
with
an
oxygen
on
the
far
right
carbon.
F
It
was
inactive
for
us,
but
yeah
yeah.
I
think
we've
got
that
thinking
about
it
was
one
of
those
ones
that
were
like.
Oh,
that
would
be
a
cool
molecule
to
make.
A
Okay,
thanks
man
and
anything
else
briefly,
you
know,
I
think
we've
got
our
hands
full
now
with
some
synthesis
that
he's
doing
and
checking
and
we're
waiting
on
moa
and
metabolic
stuff.
So
I
think
we're
in
a
good
we're
a
good
place.
We're
just
going
to
make
a
few
key
molecules
here,
particularly
now
that
we
know
that
this
guy
is
inactive.
B
A
A
Them
to
the
list
I
mean
it
is
it's
interesting.
It's
a
data
point
we
needed
and
it's
interesting.
It's
a
bit
of
a
pisser
has
to
be
said
because,
yes,
we
have
to
reevaluate
some
of
these
sar
points.
Yeah.
D
It's
all
it's
all
fun
until
your
lead
until
your
derivative,
your
your
parent
compounds,
inactive.
A
A
Okay,
really
good.
Thank
you.
That's
very,
very
helpful.
Wow,
really
good
ideas
thanks
for
coming,
we'll,
try
and
have
another
meeting
next
week
as
per
usual.
Okay,
that's
great
until
then
stay
safe.