►
From YouTube: Open Source Antibiotics Science Update July 16th 2021
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/82
On the call: Professor Matthew Todd, Dr Dana Klug, Dr Edwin Tse, Giada Sabatino, Alex Vaideanu (UCL), Prof Lee Graves (UNC Chapel Hill), Dr Flavio Emery (University of Sao Paulo), Dr Quillon Simpson (NEU), Anthony Sama (Citizen Scientist), Dr Chris Swain (Cambridge Medchem Consulting)
A
Okay
and
we've
got
a
few
things
to
do
today.
One
is
to
run
through
some
of
the
admin
data
that
we
had
last
time
and
where
we've
now
got
some
log
d
data,
I
think
so
we
can.
We
can
write
through
that
in
just
a
second
and
also
going
to
hopefully
get
chemistry
updates
from
various
people
and
asked
alex
to
come
along
and
just
say
a
few
final
words,
hopefully
about
the
talks
and
lee
is
joining
us
to
talk
about
plans
for
the
mechanism
of
action.
A
Experiments
so
lots
to
do
anyone
want
to
go
first
lee,
I
guess,
did
you
want
to
say
something
about
mechanism
of
action,
because
we
we
came
back
to
you
with
some
requests
about
experiments.
We
could
do
based
on
latest
data
just
to
go
just
to
just
to
reiterate
what
I
said
on
the
email
we
have
been
measuring,
potency
versus
mrsa
and
toxicity
and
alex's
on.
A
We
were
very
interested
in
trying
to
find
out
mechanism
of
action
stuff
and,
and
the
idea
rose
the
you
know
what,
if
the
target
is
also
mammalian
human,
is
there
a
way
that
the
experiments,
if
we
did
them
on
on
a
mrsa
experiment,
and
I'm
a
malian
cell
line,
that
we
could
maybe
extract
some
information
about
that
to
see?
If
indeed
there
is
a
human
target?
A
I
guess
that's
where
we
were
at.
We
also
haven't
yet
identified
a
compound
as
better
than
the
ones
we
sent
you
the
positive
and
the
negative
control,
and
so
I
guess
we
wanted
to
talk
about
whether
you
needed
more
compound
and
and
what
the
plan
was.
Are
you
happy
to
just
just
update
us
and
tell
us
what
what
what
gives.
B
B
Yet
I
think
that's
that's
where
I
feel
like
you
know
we
we
we
need
to
go
though,
and-
and
I
I
feel
like
there
were
some-
what
looked
like
some
pretty
promising
hits
from
the
first
set.
I
don't
know
what
other
people
have
if
anyone
else
has
followed
up
on
some
of
those
things
it's
been
a
while,
since
I
connected
with
you
guys.
A
C
B
Well,
it
would
be
a
lot
easier
for
us
to
do
these
studies
in
a
human
cell
line,
because
we
don't
have
good
access
to
mrsa
samples.
I
had
to
go
to
a
lab
next
door
and
get
those
if,
if
there
are,
if
there's
a
great
interest
in
a
human
target
potential
off
target,
we
could
certainly
do
that
in
293
cells
and
we
have
a
very
well-established
kind
of
profile
in
293
cells.
A
D
F
E
D
A
C
B
B
B
A
A
A
Right
they
may
not
have
the
ones
we
sent
to
you.
I
don't
know
we
can
we
can
catch
up
by
email,
but
based
on
the
just
on
the
last
samples
we
sent.
I
guess
we
just
wondered
if
there
was
enough
leftover
yeah,
my
tech
this
morning,
on
that
all
right,
all
right,
great,
thank
you,
and
I
mean,
if
you
know,
I'm
just
thinking
about
publication
as
well.
So,
given
that
we,
you
know,
we've
originated
this
series
in
a
as
a
an
anti-mrsa
compound.
A
It
may
not
end
up
that
way,
but
if
we,
you
know,
originated
there,
we're
gonna
need
to
have
some
data
of
the
kind.
That's
on
the
screen
there
in
a
way
that
you
are
happy
with.
So
I
mean
if
there
was
a
possibility
repeating
this
at
the
higher
concentration
that
that
would
help
publication.
I
think
I
know
it's
more.
I
know
it's
more
difficult
because
you
don't
have
the
cells
locally.
E
B
B
A
D
G
B
Yeah
they
have
a
primitive
form:
the
lawn
protease
and
the
clpp
clip
protease.
Those
are
both
proteasome-like
in
terms
of
the
barrel
structure
and
the
atpas
function,
so
they
are
like
a
primitive
proteasome,
you're,
absolutely
right
and
there's
lots
of
interest
in
compound.
In
fact,
that's
one
thing:
our
lab
works
on
compounds
that
regulate
these
bacterial
or
mammalian
homologs
of
that.
A
B
We
did
matt
by
accident,
we
we
immobilized
the
compound.
We
were
interested
in,
we
captured
the
mitochondrial
protease
clip
and
that
has
the
bacterial
homologue
that
and
our
colleagues
have
been
studying
the
bacterial
ones,
there's
a
lot
of
interest
in
both
inhibitors
and
activators
of
it,
because
they
have
growth,
inhibitory
effects
and
we're
looking
at
cancer
cells,
trying
to
figure
out
how
that
works.
But
yeah
we
used
an
affinity,
chromatography
approach
to
fish
it
out
and
that's
how
we
got
interested
in
it.
But
there's
a
lot
of
literature
on
that
area.
Actually,.
A
Okay,
that
sounds
right,
interesting,
okay,
great!
Well!
Thank
you
lee!
That's
that's
fantastic!
Just
let
us
know
if
you
have
the
compound
enough
for
the
compound
to
go
and
we
can
supply
more
if
needed
or
yeah,
I
mean
that
you
know
tim
or
karen
might
have
some
locally
I'll
check
with
those
guys.
Okay,
all
right
awesome!
Thank
you,
okay.
A
The
other
thing
I
want
to
talk
about
was
the
the
admi
data,
because
dana
has
just
added
in
what
was
it
the
log
d
data
right
you
added
in
yeah,
so
these
were
the
latest
data
that
we
got
back
and
I
guess
you
know
we're
thinking
about
well,
which
compound?
What
can
we
learn
here?
Because
last
time
we
looked
at
these
data,
we
were
struck
by
the
unfortunately
inverse
correlation
between
potency
and
clearance,
with
solubility
appearing
to
dominate
a
number
of
these
features.
A
A
If
we,
if
we
remove
that
system-
and
we
go
for
the
five
six
system,
with
essentially
identical
substituents,
so
like
865
versus
978
over
here,
we
don't
solve
the
clearance
issue
and
it's
still
fairly
simple.
Our
numbers
here,
which
of
course
you
know,
raises
the
idea
that
maybe
there
is
another
liability
in
this
compound
so,
for
example,
the
methyl
group.
A
But
then,
if
you
look
at
the
compound
next
door,
which
has
the
o
trifluoromethyl
on
it,
then
the
the
numbers
are
approximately
the
same.
But
of
course
that
could
be
because
it's
being
metabolized
again
here-
and
so
I
guess
you
know-
one
possibility-
is
a
molecule
that
combines
the
five
six
system
with
with
something
parasubstituted,
which
again
is
a
bit
like
the
ocf
iii,
which
would
resist
metabolism.
C
D
E
So
I
was
actually
very
interested
in
864
because
we've
made
that
compound
with
the
para
cyano
instead
of
the
meta
and
it
is
active,
so
I
would
really
like
to
get
abby
data
on
that
and
I've
spoken
to
laurie
and
she
said
she
does
have
the
capacity
for
testing
some
more
of
our
compounds.
So
I
think
that
one.
C
A
But
chris,
I
guess
you're
talking
about
these
in
terms
of
well.
You
know
this
still
has
the
apparent
liability
here,
but
we
that's
that's
right,
yeah,
so,
which
is
a
little
interesting.
Isn't
it
because
you
think?
Well,
if
these
I
mean
these
solubility
numbers,
I
don't
know
your
take
on
this
chris,
but
the
the
range
of
solubility
here
is
just
enormous
yeah,
with
apparently
small
changes,
giving
rise
to
very
large
differences
in
solubility.
I
mean,
if
you
look
at
these
two
compounds.
Sorry,
no!
It
wasn't
those
two
commas.
It
was
these
two.
A
So
this
is
a
difference
of
meta
versus
a
parameter
and
one
is
32
and
one
is
five.
Five
six,
I
mean
serious
differences.
Just
with
that
substitution,
I
I
mean.
Do
you
believe
that
I
don't
know
it's
difficult
to
rationalize
and
obviously
these
are
fantastic
numbers
here,
but
again
it's
I
mean
here.
I
guess
it's
a
little
bit
more
sensible,
the
the
solubility
differences
and
clearly
there
is
then
not
really
a
big
problem
with
this
group
if
your
molecule
is
soluble
enough
right.
E
D
A
D
A
Cyano
is
quite
polar
as
well
yeah,
but
for
potency
we
don't
need
something
polar
in
that
position.
We
need
something
polar
elsewhere,
don't
we
because
it
appears
to
be
true.
I
mean
the
potency
seems
to
be
tracking
quite
well
with
something
which
is
power
substituted.
I
mean
these
groups
are
really
quite
nice.
E
H
E
C
E
E
C
E
D
E
A
I
A
E
A
E
I
Yeah,
because
yeah,
okay,
I
can
see
a
few
here
in
general.
I
could
have
a
look
through
this
and
if
you
could,
let
me
know
what
has
been
sent
dana
and
I
could
send
compounds
that.
Perhaps
you
haven't
seen
or
tested,
but
I
can
still
provide
add
me
data
for
like
more
generally
speaking,
so
you
can
see
the
spr
for
the
series
as
a
whole,
if
you're
interested
in
that,
I
can
send
through
some
of
that
data
if
it
hasn't
been
done
so
already.
A
A
E
A
I
C
A
Okay,
all
right
all
right
thanks,
so
we
are
a
couple
of
targets
there
and
a
couple
of
ways
forward:
I'll
I'll,
put
actions
up
on
the
minutes,
but
trying
to
access.
Perhaps
other
compounds
here
from
our
precursor
to
try
to
improve
the
solubility
again
so
often
the
case
you're
trying
to
improve
the
solubility
of
things.
F
F
F
Where
I
hear
I
couldn't
calculate
an
ic50
and
for
mtg
we
can,
and
actually
the
inhibition
is
quite
a
lot
higher
than
what
we
find
by
resizuring.
So
then
the
other
thing
we
wanted
to
do
because
this
is
actually
typically
the
way
we
do.
A
toxicity
assay
in
our
lab
is
seed.
A
sort
of
smaller
number
of
cells
allow
them
to
reach
exponential
phase.
So
typically
here
I
incubate
it
for
three
days
before
treating
then
we
treat
it
for
24
hours
and
then
we
allow
the
cells
to
recover
so
as
to
see.
F
If
then
they
actually,
if
they,
if
the
compound
is
actually
just
cytostatic,
it
just
holds
proliferation
or
it
actually
cytotoxic.
And
if
the
cells
then
don't
recover,
then
that's
the
case.
So
I
haven't
done
a
great
deal
of
these
because
they're
longer
than
this
one-
and
I
haven't
had
much
time-
sorry,
but
what
I
can
say-
and
I
wanted
to
clarify
this
issue
for
it
98983.
F
So
I
did
both
readouts
and,
as
you
can
see,
I
get
fairly
similar
values
versus
6050
and
the
standard
error
is
much
lower.
So,
for
me,
I'm
a
lot
more
confident
in
this
data,
also
because
it
from
our
point
of
view,
it
makes
more
sense
to
do
it
this
way.
So
in
terms
of
the
order,
neither
by
recess
or
mtc
that
doesn't
change
and
sort
of
yeah,
they
still
seem
to
be
quite
toxic,
at
least
the
ones
that
I've
tested.
F
Again,
it's
just
a
difference
between
the
actual
protocol,
also,
rather
than
seeding.
The
cells
here
I
see,
did
5000
cells
in
48
hours
because
I'm
doing
the
assay
in
a
96
well
plate
the
quad
protocol
used
it
384
well
played
so
they
seated
5000
only
for
24
hours,
but
because
I'm
using
a
larger
surface
area,
I
allowed
them
to
grow
a
bit
longer
and
then
just
incubate
it
with
the
compound-
and
I
said
after
24
hours
for
one
week.
F
E
F
F
D
F
So
yeah
I
haven't
done
every
one
of
them,
but
for
by
mtc.
That's
not
really
that
different.
But,
as
I
said
before
here,
the
standard
error
is
quite
high,
so
20
to
25,
whereas
this
is
like
one
or
maybe
less
than
something
like
that
yeah
so
by
the
this
readout,
and
that
could
be
due
to
various
practical
things
to
do
with
the
two
assays.
As
I
said,
recession
is
a
fluorescence
readout.
F
It's
a
you
know
you
have
a
higher
dynamic
range.
You
have
well
the
opportunity
to
not
have
to
wash
in
between.
So
you
you,
you
add
the
the
die
and
just
read
in
the
well,
whereas
with
the
mtt,
it's
often
you
have
to
remove
the
solution
wash.
You
have
to
add
the
mtt
solution
and
then
remove
again
and
then
add
the
mso
to
stabilize
the
crystals.
So
there's
a
lot
more
error
that
could
come
from
these
many
steps
so
or
you
could
lose
cells
because
you're
aspirating
many
times
yeah.
A
F
F
A
F
A
A
A
Okay
and
then
so
yeah,
I
wanted
to
also
mention
the
compounds
that
were
sent
through
from
nau,
which
is
great,
so
we
are
the
lucky
recipients
of
these
compounds
which
have
just
arrived
and
which
can
be
included
in
the
next
round
of
potency
evaluation.
So
thank
you
very
much,
lori
and
colin
for
sending
those
over
you're
not
sharing
just.
I
A
G
Just
just
a
brief
update
from
my
my
side,
I
believe
now
we
have
some
examples
from
the
wallet
series,
but
we
are
not
very
successful.
You
know
having
good,
very
good
yields
problems
on
purification,
so
we
have
them,
but
in
just
a
small
amount,
maybe
I
will
contact
laurie
and
and
the
guys
and
their
team
to
to
help
me
and
how
to
purify.
I
think,
last
to
last
meeting
I
participated.
G
G
G
Yeah
yeah
there
is
someone,
it's
a
phenyl
groups
like
a
benzene
like
the
ones
we
are
working
on
and
we
have
to
alkylate
that
to
to
keep
working
with
the
same
kind
of
substitution
and
alkylation
is
is
not
working
that
well
for
us.
I
will.
I
will
try
to.
I
try
another
method
now,
just
copper
alkylation.
I
read
calculation
now
which
mean
which
maybe
could
work
better,
but
it
would
be
a
different
kind
of
chemistry
from
the
simpler
substitution.
I
I
G
A
I
I
So
I
sort
of
we
had
an
undergraduate
working
on
these
and
I
took
over
this
week
to
sort
of
finalize
because
he's
no
longer
with
us,
so
these
alkylations
have
all
gone
forward
conditions
up
the
top
here.
For
that
I
tend
to
find
that
the
best
way
to
purify
these
compounds
is
using
a
biotaj
c18
column,
so
on
about
100
milligram
scale,
I'm
using
the
30
gram
c18
column
to
do
the
reverse
phase
purification.
I
If
you
have
smaller
alkyl
chains
like
we
are
not
able
to
do
that,
we
send
it
away
to
to
get
professionally
purified,
so
I've
I've
been
able
to
isolate
these
these
four
that
we
have
down
the
bottom
here.
The
exception
is
this
final
compound
here,
there's
only
a
few
milligrams,
it
looks
like
I'm
waiting
to
remove
the
last
of
the
water
from
the
column.
A
I
mean
add,
me
is
always
really
useful,
particularly
in
this
case,
if
we
can,
if
we,
if
we
can,
if,
if
we
can
include
in
the
measurement
log
b
that-
and
if
that
is
part
of
your
add
me
screen
normally
yeah,
we
get
a
full
tier
one,
okay.
So
then
this
would
be
particularly
useful
because
it
has
the
author
substituent,
which
should
help
with
solubility
right,
because
it's
deep
plane
arises.
I
Definitely
does
so
I
can
just
as
a
little
bit
of
extra
information
as
part
of
our
efforts.
I've
been
growing
crystal
quality
structures
for
these,
so
these
are
some
some
x-ray
crystal
structures
that
we've
got
for
these
compound
series
and
a
bit
of
the
add
me
to
go
alongside
that.
Beautiful
and
yeah
definitely
improves
the
the
solubility
with
that
orthomethoxy
compound.
As
you
can
sort
of
see
here,
it's
it's
non-linear.
I
I
think
it
precipitated
out
of
the
the
top
end
of
the
curve,
but
yeah,
unfortunately,
for
us
it
completely
kills
potency
when
you,
when
you
twist
that
ring
so
if
you
are
able
to
get
potency
with
with
that,
then
there's
definitely
avenues
to
improve
solubility
through
functionalization
of
that
period.
Aisle.
I
I
I
K
A
You
know,
normally,
you
associate
you
know
big
groups
which
clash
with
giving
these
large
angles
here.
You
have
heteroatoms
which,
which
don't
necessarily
have
h's
sticking
out,
so
the
oxygen
doesn't
have
an
h
sticking
out
and
the
nitrogen
can
be
either
way
around
and
not
have
something
pointing
at
the
other
ring.
So
it's
nice
to
see
that
it
is
still
a
dramatic
impact,
in
fact
yeah.
So.
I
We've
also
done
some
energy
minimizations
of
these
two
compounds
as
well
and
at
a
b3
lip
level.
You
actually
see
the
pure
dial
rotates
completely
around
and
forms
an
nh
bond
with
with
the
amine,
so
is
obviously
like
x-ray.
The
the
caveat
here
is
that
it's
in
the
solid
state
and
the
solution
state
may
behave
very
differently,
but
the
then
you
got
to
then
sort
of
weigh
that
with
the
the
the
qm
models
that
we
have
as
well
and
how
believable
they
are.
I
A
I
A
K
Yes,
so,
basically,
last
week
we
synthetized
the
red
compound,
but
we
didn't
obtain
like
100
pure,
but
we
have
only
90
pure
and
the
eel
was
not
really
good.
So
we
tried
also
to
obtain
the
same
compound
by
different
intermediates
by
different
steps,
but
as
well,
we
didn't
obtain
the
desired
product,
so
the
plan
is
try
to
purify
again
the
compound
the
the
red
compound
and
test
it
and
next
week
try
to
optimize
the
the
synthetic
root
in
order
to
obtain
more
compound
or
more
pure
compound.
A
C
E
So
yeah,
I'm
still
on
the
one
pots.
It
looks
like
five
minutes
in
the
microwave
as
opposed
to
30
is
actually
helping
so
and
then
it's
just
the
purification
I
they're
just
they're
horrible
to
work
with
really,
but
the
crude
is
like
black
and
it's
gross,
but
I
have
done
the
pyrrole
a
normal
phase,
column,
the
nmr
and
the
lcms.
Look
okay,
but
the
material
is
still
black.
So
I
think
it
does
need
another
purification,
but
I'm
I'm
hopeful
about
that.
C
E
I
I'll
send
you
the
graph
for
the
conditions
that
we
use.
It's
a
generic
method.
I
just
single
it's
sort
of
almost
a
catch
and
release
method,
so
it
will
precipitate
out
at
the
top
of
the
column
you
wash
out
all
the
impurities
and
when
it
gets
to
a
certain
percentage
it
redissolves
and
puts
it
out
of
your
compound.
It
makes
the
the
purification
of
the
one
pot
trivial.
E
Yeah
well
so
the
thiazole
one.
I
actually
went
to
purify
that
reverse
phase
and
ended
up
recovering
it,
just
from
washing
it
basically
with
methanol,
but
that's
not
working
for
the
peril
derivatives.
So
the
solubility
of
those
does
seem
to
be
a
little
bit
different,
but
yeah.
If
you
want
to
send
me
that
I
can
give
it
a
try
for
sure.