►
From YouTube: Open Source Antibiotics Science Update Dec 18 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/49
On the call: Professor Matthew Todd, Dr Dana Klug, Dr Edwin Tse, Giada Sabatino (UCL), Dr Chris Swain (Cambridge MedChem Consulting), Anthony Sama (citizen contributor), Lori Ferrins (Northeastern University)
A
All
right
welcome
to
the
pre-christmas
meaning
of
open
source
antibiotics
series,
2
and
let
me
share
the
screen,
which
has
the
issue
on
it,
that
I
just
posted
thanks
for
coming
along
everybody.
I
guess
the
thing
that
we
want
to
talk
about
mostly
would
be
the
new
potency
results
which
came
in
from
paul
stapleton's
lab,
which
I've
shown
here.
So
here
are
the
two
controls
you
can
get
it
all
on
screen.
That's
good
here
are
the
two
controls
h1
820
and
which
is
fine.
They
gave
you
know
the
same.
A
Were
these
retested
or
they
are
those
old
data?
Okay,
we
test
them
great.
So
there's
continuity.
That's
good,
and
here
are
the
results.
I
haven't
had
time
to
assimilate
this,
but
there
were
some
things
here
which
were
kind
of
interesting.
I
mean
for
me.
The
big
thing
I
think
was
that
we
varied
the
position
of
the
nitrogen
on
this
ring,
switching
it
around
a
little
bit,
including
a
ring
with
the
two
piridial
and
another
nitrogen,
but
switching
it
around
and
lose
potency
when
we
do
that.
B
A
The
kind
of
compound
that's
active
that
we
expect
to
be
active,
so
that's
very
sensitive,
but
this
is
an
interesting
one,
obviously
that
we
maintain
it
with
another
nitrogen
and
we
still
lose
it
so
fairly
sensitive
that
that
doesn't
mean
that
I
mean
it's
not
sufficient,
obviously,
for
activity,
but
it's
it's
necessary
doesn't
mean
that
other
cycles.
I
guess,
with
a
with
a
coordinating
atom.
There
wouldn't
be
a
good
idea,
but
there
is
obviously
you
know
significant
sensitivity.
There.
A
That's
number
one
number
two
for
me
that
stood
out
in
terms
of
importance
was
was
this
guy,
which
has
the
alternative
ring
system
that
we've
been
talking
about
and
which
has
activity,
which
is
interesting
unless
I'm
missing
something
that's
quite
useful.
A
A
third
minor
thing
is
just
the
sensitivity
of
the
substitution
to
being
para,
so
you
know
the
previous
compound
with
the
methyl
and
the
power
position
not
shown
here,
but
was
potent
and
as
you
move
that
metal
round
you
lose
the
potency.
A
D
So
the
yeah,
the
reason
I
wanted
to
make
the
pericoro
and
then
the
dichloro
was.
I
was
looking
at
this
topless
analysis
where
you
do
a
batch-wise
analysis.
I
think
we've
made
all
the
ones,
the
first
tier
that
they
recommend.
So
then
what
you
do
is
sort
of
put
them
in
order
of
potency
and
go
from
there,
and
I
haven't
had
a
chance
to
do
that
analysis.
But
I
will
and
then
I
can
post
it,
and
it
does
give
you
some
suggestions
of
what
to
make
next,
which
would
be
yeah.
A
D
E
B
F
B
Assume
that
and
the
paradigm
ethyl
aniline
boronic
acid
is
probably
pretty.
B
B
The
978,
so
I
was
wondering,
can
we
fluorinate,
maybe
science,
maybe
even
cyano,
on
that
position.
D
A
Yeah
I
mean
you're,
I
mean
yeah.
The
comment
about
trying
to
break
through
potency
is
is,
is
relevant
here
in
the
sense
that
you
know
each
time
we
make
something.
Of
course
it
takes
time
and
effort,
and
so
I
just
I
yeah.
I
wonder
if
the
the
changes
that
we
we
are
looking
for,
because
I
mean,
besides
being
you,
know,
methodical
about
it
with
with
things
like
a
topless
analysis,
should
be
slightly
bolder
changes.
I
mean
an
nh2.
There
would
be
a
big
change
in
place
of
the
cyan
chloroflora.
A
Maybe
if
it's
easy,
but
that's
not
a
substantial
change,
I
suppose
I
mean
what
you're
talking
about
dana
is
you
know,
improvement
of
two
or
order
of
magnitude
better
right,
I
mean
that's
what
you
wanted
to
see
with
some
of
this
and
yeah.
We
are
kind
of
flat
here
still
and
we
can't
put
infinite
resources
into
it.
C
A
What
let
me
just
go
back
to.
D
B
D
D
A
Yeah
and
and
chemistry-wise,
how
is
that?
How
is
that?
Looking?
Is
that
something
we
can
simply
access.
D
I
think
so
I
mean
I
think
it
would
be
kind
of
interesting
to
see
if
we
can
just
do
the
chemistry
on
that
compound,
but
otherwise
we
would
have
to
go
back
to
the
beginning.
Maybe.
A
I
was
just
thinking
about
the
cause
that
you
sent,
laurie,
which
I
was
going
to.
E
The
forgive
me
for
not
remembering
so
we
noticed
that
there
was
some
puri.
Obviously
pyridine
is
the
two
paradile
is
the
one:
that's
there
the
most
often
then
you've
got
the
there
was
the
pyrimidine.
Have
you
done
any
substituted,
pyrazoles
or
imidazoles.
A
Yes,
I
don't.
C
E
Yeah
I
mean
so
we're
about
to
start
looking
at
so
eight.
I
think
it's
eight
six,
six,
I'm
really
glad
my
video
is
currently
off
because
you
would
have
all
had
a
lovely
view
of
my
forehead,
so
I
think
with
866
we're
about
to
try
something
similar
to
that,
but
actually
like
putting
the
tetrahydropyramid
in
place
of
the
methyl,
which
is
not
foreign
yeah.
So
we're
trying
we're
thinking
about
something
like
that.
I
think
we're
gonna.
E
D
As
our
I
I'm
a
bit
skeptical
of
those
five-membered
rings
in
that
position
I
mean
so
none
of
these
are
exact
matched
pairs
to
anything
else
that
we
have,
but
yeah
they're,
similar
and
you
can
see
any
five-membered
ring-
is
inactive
that
you
try
to
put
down
there,
so
you
don't
have
any
activity
with
any
of
them.
Basically,.
A
G
And
sorry,
if
I
interrupt
trying
something
with
like
something
bigger,
maybe
five
membering
is
low
is
too
small
and
six
is
fine
with
seven.
Maybe.
D
I
could
try
substituted
to
pyridol,
but
I
don't
know
how
synthetically
accessible
that
would
be,
but
we,
I
think,
put
a
naphthal
there
if
I'm
not
mistaken,.
D
E
B
C
B
E
E
I
mean
I'm
thinking
it
would
need
to
be
saturated,
yeah.
B
It
would
be,
it
would
have
to
be
a
small
saturated,
nitrogen
heterocycle
but
or
nitrogen
yeah.
I
don't
know
I
really
morphaline
in
that
position.
I
don't
know
so
we
haven't,
we
haven't
tested
that
have
we
essentially
could
that
be
done
through
palladium
catalyzed,
like
book
heart
wig
on
that
core,
or
is
that
too
bulky
and
the
whole
thing
would
not
work
or
do
we
have
to
start
from?
Could
we
start
from
978,
or
would
we
have
to
go
back
a
couple
steps.
B
No
we're
talking
about
978,
popping
nitrogen
containing
substituents
on
that
chlorine.
A
D
C
B
You
can
try
always
sprinkle
steam
substance
popping
off
the
chlorine
for
an
iodine,
but
it
depends
a
lot
on
the
core
itself.
B
A
For
if
we
did
try
and
do
a
just
sorry
got
distracted
by
thinking
about
a
sanctuary
heterocycle
in
place
of
the
pyridine,
if
we
did
do
something
like
that,
how
would
we
make
something
of
that
kind
if
it
was
like
a
a
paradigm
or
something
of
that
kind?
In
this
position,
I
don't
know
if
that's
even
worth
it,
but
I
mean.
C
A
B
Do
we
know,
though,
if
that
n-linker,
on
the
top
that's
going
to
be
given
by
the
one-pot
procedure,
affects
potency
in
any
way?
I
know
ed
and
ed
tried
making
the
the
standard
core
with
the
tahlidine
substituent,
but
you
know
because
we
could
be
losing
potency
on
the
one
pots.
Just
from
that
end.
Linker
that's
formed
on
top
from
the
eisenhower
trial.
B
C
E
E
We
have
actually
put
a
a
methylene
linker
between
the
peridol
and
the
core.
I
just
looking
at
how
we're
trying
to
find
how
we
did
that
between
the
two
rings.
Yep,
we
tried
pushing
it
out
a
bit
to
see
if
that
would
have
any
effect.
A
Yeah,
if
there's
a
nice
chemistry
there
that
you
know
about
already
that
would
be
useful
or
if
there's
something
we
can
do
just
to
fill,
that
little
hole.
B
E
Yeah
we
we
can
either
make
them
more
if
they're
commercially
available
by
them.
One
of
the
things
that
oh
no,
it's
fled
my
mind,
never
mind,
I'm
sure
it
will
come
back.
I
A
I've
just
completely
forgotten
what
I
was
going
to
say:
sorry
so
for
daniel,
if
you
were
able
to
just
post
on
that
synthetic
approach
again
and
and
then
talk
about
some
of
the
materials
that
are
available,
that
might
take
us
into
different
places
that
we
want
to
go.
That
would
be.
That
would
get
everyone's
minds
thinking
about
what
we
might
want
to
make.
D
A
A
Particularly
well
suited
for
the
nine
seven
eight
chris
was
talking
about
that
might
prioritize
one
rather.
B
A
E
That
was
what
I
was
going
to
say
the
next
batch
of
compounds
that
we
just
sent
you
where
we've
got
the
and
alkyl
derivatives.
I
think
that
could
actually
be
quite
interesting
in
terms
of
whether
you
maintain
any
kind
of
activity,
if
you,
if
I
guess
I'm
wondering
if
the
nh
is
maybe
bad
and
by
blocking
that
it
kind
of
is
a
little
bit
more
similar
to
the
core
and
the
scaffold
that
you've
been
using.
E
Like
with
six
seven,
two,
nine,
just
just
the
fact
that
we've
got
those
different
alkyl
groups,
I'm
I'm
kind
of
curious
to
see
if
that
brings
it
sort
of
a
little
more
back
in
line
with
what
you've
been
testing,
because
you
don't
have
that
free
nh,
like
we've
sent
with
most
of
the
components
that
we've
sent
to
you
so
far.
I
see
okay.
E
So
I've
just
I'm
just
looking
through
the
procedures,
we
still
just
made
the
an
aldehyde,
so
we
actually
built
in
the
methylene
linker
between
the
core
and
the
pyridine.
But
I
mean
we
actually
used
a
parasol,
and
so
we
have
a
methylene
there,
but
we
did
it
still
via
the
same
one
pot
that
we've
used
before
so.
Oh
yeah,
probably
not.
E
Yep
inserting
a
methylene,
but
it's
probably
not
going
to
get
you
to
your
to
a
saturated
derivative
right.
Okay,
okay,
I
see.
A
C
C
E
B
You'd
have
to
nuke
it
with
a
ch3i
and
see
what
you
get
out
at
the
end.
A
C
A
So
many
nice
things
I
mean,
I
think,
the
the
yeah
the
earlier
comment
in
the
interest
about
trying
to
get
an
advance
intermediate
which
allows
you
know
the
attachment
of
a
bunch
of
different
things
is
a
really
good
one.
If
we're
trying
to
be
bold
about
the
changes.
Making
a
ring
saturated
is
a
bold
change,
but
it
can
be
difficult
to
do
unless
you
you
happen
to
get
lucky
with
a
procedure
like
the
one
you
just
mentioned.
A
H
Yeah,
so
I
did
a
gram-scale
reaction
to
that
and
got
about
560
megs
right.
I
think
I,
like
this
reaction,
is
pretty
much
50
every
time.
So
I
think
in
total
I've
got
about
800
now.
B
D
Yeah
and
it's
I
think,
alvaro
made
it.
B
But
did
it
have
that
problematic
top
benzylene
dioxide?
No.
B
A
Okay,
we
can
draw
up
some
plans
yeah.
So
if
you're
happy
to
think
about
some
potential
starting
materials,
then
we
can.
We
can
pursue
that
discussion,
thinking
about
advanced
intermediates
of
this
kind
and
maybe
playing
around
with
a
little
bit
of
chemistry
if
ed
can
sacrifice
some
of
those
a21,
for
example,
trying
to
reduce
this
ring,
perhaps
not
a
terrible
idea.
A
And
but
maybe
even
I
mean,
I
think
that
I
think
the
five-membered
ring
aromatic
nitrogen-containing
ring
in
place
of
the
pyridal
seems
risky
based
on
what
we
know,
and
maybe
it's
better
to
play
with
this.
E
A
E
I
guess
I
guess,
when
I'm
looking
at
these,
so
to
go
back
to
matt's
point
before
having
the
nitrogen
in
the
same
position
as
the
two-paradile.
Yes,
but
then
you've
also
got
additional
nitrogens,
which
were
unfavorable.
E
A
So
I
mean,
if
you
you
want
a
nitrogen
which
is
which
is
coordinating
so
an
nh
acceptor,
not
donor.
So
you
need
something
like
a
an
oxazole
rather
than.
E
Yeah,
but
I
guess
I
was
thinking
if
you
had,
the
the
thiazole
would
be
better
because
sulfur
is
more
like
carbon.
A
I
think
you've
tried
what
I
would
have
gone
with
next
and
and
sorry
this,
the
rest
of
the
call
we'd
expect
to
be
active.
Do
we
just
because
of
what
we
know
so
hang
on
a
second
sorry,
I
know
I
know
scroll
other
people
twirling
is
really
irritating,
but
there's
that
meta
fluoroaniline
at
this
position.
A
So
this
is
the.
E
A
E
A
Not
great,
but
it's
something
so
if
it
was
going
to
be
better
you'd
expect
to
be
better
than
that
yeah,
I'm
sorry
roughly!
You
can't
definitely
conclude
because
we
haven't
got
the
right
compound,
but
you'd
think
it
would
show.
C
Something
one
thing
that
does
occur
to
me
and
is
that
is:
could
could
we
replace
the
central
part
with
a
a
bentamidazole
so
you're
moving
the
nitro,
the
nitrogen,
the
brig
bridgehead
to
the
next
thing
over.
C
So
if
you
take
well
an
example
here
would
be
the
first
one
840.
yeah,
but
it
would
forget
about
your
substituent
at
the
top
left
for
the
moment.
Move
that
nitrogen
one
position
over
to
the
left
you'd
have
to
move
the
there
were
bonds
around,
but
you
would
end
up
with
a
two-hour
benzomidazole.
Oh.
E
I
feel
like
there's
a
lot
of
chemistry
around
the
periodizer
purity
purezolo
pyridine,
even
okay.
I've
only
had
one
coffee
this
morning,
so
I'm
just
moving
that
that
same
nitrogen
bit
down
so
that
it's
next
to
the.
E
Side
by
side,
yeah,
yeah
backwards,
yeah
side
by
side.
I
feel
like
that
also
could
be
relatively
amenable
to
diversification.
A
I
mean
so,
I
guess
yeah
I
mean
chris
is
talking
about
just
alkaline
bunch
of
benzyl
compounds,
right
yeah,
which
would
be
very
sweet
and
adding
in
substituents
of
the
middle
carbon
is
meant
to
be
easy.
A
But
one
of
my
other
students
would
maybe
disagree
with
that
assessment,
because
she's
been
trying
to
do
that
for
one
of
the
open
source,
malaria
projects
and
it's
not
straight
forward.
Okay,
but
I
think
if
you
can
buy,
you
know
sort
of
br
well
benzemidazole
and
then
try
and.
C
I
I
think
you
know
the
idea
of
perhaps
looking
at
these
cores,
and
particularly
with
the
idea
of
synthetic
accessibility
in
mind,
might
be
worthwhile
a
bit
of
literature,
work.
A
A
I
mean
in
terms
of
sorry
single
item
changes,
maybe
in
a
core
but
not
on
the
periphery,
is
where
we
need
to
be
going,
because
I
think
you're
right
dana.
I
think
we've
got
to
try
and
hit
something
better
than
this
if
we're
going
to
get
anywhere
with
these
compounds.
H
Oh,
so
we
can
buy
two
pyridol
benzamidazole
from
florican.
A
A
A
Great
good
stuff,
okay,
all
right,
that's
been
very
useful
thanks
for
all
of
that,
that's
really
good.
A
All
right
now
I
mean,
I
think,
that's
that's
pretty
much.
The
the
main
thing
that
I
wanted
to
talk
about
is
is
where
those
data
and
what
we
could
take
away
from
them.
So
that's
been
extremely
useful.
A
Cytotoxicity
is
still
underway
done
right
and
you
haven't
heard
about
anything
back
okay,
which
has
taken
a
while,
but
I
think
some
of
our
internal
searching
tasks
in
the
school
of
pharmacy
have
maybe
taken
priority
recently.
Do
you
have
any
synthetic
chemistry
update?
I
mean
you've
been
wrapping
things
up
right,
because
the
lab's
closing
down.
A
Great
okay,
which
is
ready
for
heifer
if
they
need
it.
That
was
one
of
the
reasons
we
were
doing
it,
but
it
could
also
be
for
some,
you
know
late
stage,
functionalization,
okay,
great
and
then
on
this
page
there
are
a
bunch
of
other
things
which
are
just
assigned
to
people
but
which
are
not
chemical,
necessarily,
not
synthetic.
So
just
some
things
to
do
with
documentation
and
and
fixing
up.
You
know
the
various
things
so
I've
assigned
everyone
to
those
things
down
here.
This
is
a
new
issue.
A
So
sorry,
everyone's
got
a
little
bit
of
pleasure,
though,
and
and
it's
on
me,
I'm
going
to
try
and
and
just
draft
up
a
another
newsletter
before
christmas,
because
it's
always
nice
to
have.
You
know
pre-christmas
things
to
sort
of
summarize
where
we're
up
to
and
I'll
try
and
do
that
next
week,
just
for
fun.
A
The
one
thing
I
was
going
to
say
is
just
to
to
thank
you
lori
for
the
shipment
of
the
compounds,
which
are
in
our
fridge,
which
is
looking
really
good.
So
that's
really
great.
You
know
just
to
acknowledge
that
contribution
as
being
it's
been
very
valuable.
So,
thank
you,
for
that
also
received
is
the
starting
material
for
the
compound
that
we're
talking
about
in
the
merlions
project.
So
that's
also
really
great.
Thank
you
and
I
mean
we'll
get
these
tested.
You
know
with
any
other
compound
in
january.
First
thing:
yep.
A
A
And
so
one
of
the
one
of
the
things
here
for
you
dana
was
just
to
make
sure
that
those
are
put
on
somewhere
central
right
in
the
molecule
donations
page.
I
think
they're
looking
really
good.
If,
if
we're
all
happy
to
sort
of
go
ahead
with
those
that
all
right,
okay,
I
mean-
I
think
it's
a
really
nice
thing
that
we're
doing
and
actually
these
issues
are
coming
up
in
other
projects.
A
In
fact,
and
I'm
kind
of
directing
people
to
to
these
terms,
because
people
are
thinking
about
the
same
questions
which
is
quite
interesting,
so
that
will
hopefully
make
things
simpler
and
then
we
can
start
going
out
to
people
and
saying
well,
you
know
how
about
it.
A
All
right,
but
I
mean
other
than
that-
I
think
that
was
everything
that
was
important
if
people
can
just
keep
an
eye
on
some
of
these
actions
and
try
and
clear
them
if
they
have
some
time
between
make,
of
course,
some
dessert
you
know
otherwise,
so
that's
it.
I
think.
That's
everything
that
we
wanted
to
talk
about
today,
which
is
really
very
helpful.
A
A
Be
on
my
way
to
being
a
pharmacy
tech,
uh-huh,
really
yeah,
uh-huh,
okay
as
well!
That's
well,
you've
got
some
final
final
exams
coming
up
or
something
right
now,
just
starting
actually.