New bb build fuel economy

When talking about fuel economy, there are several kinds...
1) steady state
2) City
3) hiway
4) average
As to #1;
If it takes 35hp/NET to maintain 65mph in your A-body, then it will take that, no matter what engine you install or how low/ how high, you rev it. All you can do for fuel useage is reduce the internal friction inside the engine, so that more of your Gross hp becomes Net.
The 400 has the biggest bores of all Mopar passenger car engines, so reducing internal friction is gonna be a chore. Making it a 451 is just making matters worse
as for #2
Every time your rpm increases or your speed increases, that costs power, over and above the "steady-state", so fuel economy goes down
as for #3
Hiway is usually thought of as steady state; but if the terrain changes in elevation or the road surface changes, or there are turns involved, those things all cost power, which reduces your economy.
as to #4
the bigger the engine, the more internal friction it will generate. And friction costs power, which reduces fuel economy. Anytime that big engine sees an increase in load, it has to generate enough power to overcome it's internal friction, in addition to that required for the increase in load or rpm or speed. Hence, the average fuel economy of the big 451, will always be less than it would be with a smaller engine
This is irrespective of it's absolute-power.

One of the fastest ways, possibly the single worst way, to lose fuel-economy, is to have lousy cylinder pressure. Not a hope in hell would I build a low-pressure engine for fuel economy.
The Second fastest way, to lose fuel-economy, is to not have adequate Cruise-Timing. With the factory timing controls, it is impossible to supply the engine with enough Cruise-timing below about 2200rpm, no matter how much you modify that timing control, and still be able to floor the pedal. So cruising in double overdrive, geared to 65=1400rpm is not gonna get you the fuel-economy numbers that you crave or imagine. The engine will cruise at 1400 no problem; (even a 318 can make 35hpNet at 1400rpm;) but the engine, any engine, just won't get enough timing at 1400, with the factory-type ignition system, to make it worthwhile, in terms of fuel-economy versus dollars spent.
OK I better unpack that a bit. All engines have a point after TDC to best transfer the Force of the expanding gasses to the crank,where it will NET the best result as to power/torque. All your timing controls are designed to hit that mark under as many circumstances as possible. This works reasonably well in stock configuration, because the cruise-rpm in stock configuration is gonna be in a fairly small window, plus/minus about 10%. So
When fuel economy is the primary goal, then you need;
1) a small bore to stroke ratio; small bore for less friction, and long stroke for effective compression distance after the intake valve closes, but more importantly for Power-extraction before the exhaust valve opens. So,like
a 225 for instance which is 3.40/4.125=0.82! or maybe
a 273 which is 3.63/3.315=1.095, or maybe even
a 360 which is 4.00/3.58=1.117.
Versus ; your contemplated
451 which is 4.34/3.75=1.157, or ouch
a 400 which is 4.34/3.335=1.30 (no wonder they suck gas)
2) as few cylinders as possible, to make the required cruise horsepower, (like a 225 for instance) and have enough hp left over to get up to the Cruising speed, in a reasonable period of time like a 273, to not be an accident waiting to happen. and
3) you will need a stand-alone programmable, Timing Computer. And
4) more than a 2bbl carburator; the very least you will need, is a spreadbore with tiny Primaries. And
5) as much cylinder pressure as the fuel will support without detonating. And
6) long-tube small-pipe headers with a cross-over, to pump up the torque, but these are probably optional if the exhaust manifolds are Not chokes.
7) maybe one of those tail-pipe extractor turbine thingies, lol, ..... kidding!
8) a manual trans is worth about 10%
9) an overdrive is worth about 50% of the percentage in rpm reduction. So if the rpm reduction is 20% the increase in fuel economy to be expected is .20 x .50= .10= 10%; hardly worth the thousands of dollars they cost. Break-even might be a decade or more.

if you wanna talk about performance with economy, that is a separate discussion.