The following presents the structure optimization process of some lead compounds or drugs A~F:

<MultiModal>![This image contains the optimization process of six drugs, namely: A. `ClC(C=C1)=CC=C1N2C3=NC=NC(NN4CCCCC4)=C3N=C2C5=C(Cl)C=C(Cl)C=C5` optimized to `ClC(C=C1)=CC=C1N2C(C3=C(Cl)C=CC=C3)=NC4=C(N=CN=C42)N5CCC(NCC)(C(N)=O)CC5` ;B.  `ClC1=CC=C(O[R])C(NC2=NC(C([O-])=O)=CS2)=C1` optimized to `ClC1=CC=C(C([R])=CN2C3=NC(C([O-])=O)=CS3)C2=C1` ;C.  `CNC1=NN=C(C)C2=CC=CC=C21` optimized to `CNC(C1=CC=CC=C1NC)=O` ;D.  `OC(C(C)C1=CC(C(C2=CC=CC=C2)=O)=CC=C1)=O` optimized to `OC(C(C)C1=CC(C(C2=CSC=C2)=O)=CC=C1)=O` ;E.  `CCCCNC(NS(=O)(C1=CC=C(C=C1)C)=O)=O` optimized to `CCCCNC(NS(=O)(C1=CC=C(C=C1)Cl)=O)=O` ;F.  `O=C(NC1=CC=C(Cl)C=C1C(NCC2CCCCC2)=O)C3=C4C=CC=CC4=CC=C3` optimized to `O=C(NC1=CC=C(Cl)N=C1C(NCC2CCOCC2)=O)C3=C4C=CC=CC4=C(CS(C)=O)C=C3` ](/media/uploads/887244e6-0129-4253-ae75-9a4b0011151f.png)</MultiModal>
It is known that the above optimization involves the following main purposes:

1. Reducing compound lipophilicity
2. Bioisostere replacement
3. Fixing the molecular conformation to the active conformation
4. Improving drug-likeness without changing the conformation
5. Improving drug metabolic stability

Please determine the main purpose corresponding to each optimization process (there may be multiple optimization purposes, please select the most important purpose from all possible optimization purposes), and calculate the value of $z$:

$$
z=\dfrac{\text{Product of the serial numbers of the optimization processes corresponding to A, C, and E}}{\text{Sum of the serial numbers of the optimization processes corresponding to B, D, and F}}
$$

Please select the correct option, requiring the option to be within 1% of your calculated result, otherwise select option A: All other options are incorrect.
以下呈现了一些先导化合物或药物的结构优化的过程 A~F：

<MultiModal>![这幅图包含了六个药物的优化过程，分别为：A. `ClC(C=C1)=CC=C1N2C3=NC=NC(NN4CCCCC4)=C3N=C2C5=C(Cl)C=C(Cl)C=C5` 优化为 `ClC(C=C1)=CC=C1N2C(C3=C(Cl)C=CC=C3)=NC4=C(N=CN=C42)N5CCC(NCC)(C(N)=O)CC5` ;B.  `ClC1=CC=C(O[R])C(NC2=NC(C([O-])=O)=CS2)=C1` 优化为 `ClC1=CC=C(C([R])=CN2C3=NC(C([O-])=O)=CS3)C2=C1` ;C.  `CNC1=NN=C(C)C2=CC=CC=C21` 优化为 `CNC(C1=CC=CC=C1NC)=O` ;D.  `OC(C(C)C1=CC(C(C2=CC=CC=C2)=O)=CC=C1)=O` 优化为 `OC(C(C)C1=CC(C(C2=CSC=C2)=O)=CC=C1)=O` ;E.  `CCCCNC(NS(=O)(C1=CC=C(C=C1)C)=O)=O` 优化为 `CCCCNC(NS(=O)(C1=CC=C(C=C1)Cl)=O)=O` ;F.  `O=C(NC1=CC=C(Cl)C=C1C(NCC2CCCCC2)=O)C3=C4C=CC=CC4=CC=C3` 优化为 `O=C(NC1=CC=C(Cl)N=C1C(NCC2CCOCC2)=O)C3=C4C=CC=CC4=C(CS(C)=O)C=C3` ](/media/uploads/887244e6-0129-4253-ae75-9a4b0011151f.png)</MultiModal>
已知以上优化涉及到以下几个主要目的：

1. 降低化合物亲脂性
2. 生物电子等排体替换
3. 固定分子构象为活性构象
4. 不改变构象同时提升药物类药性
5. 提升药物代谢稳定性

请你判断每个优化过程所对应的主要目的（有可能有多重优化目的，请你从所有优化目的可能性中选出最为主要的目的），并计算以下 $z$ 的值：

$$
z=\dfrac{\text{A、C、E所对应优化过程序号乘积}}{\text{B、D、F所对应优化过程序号的和}}
$$

请你选择正确的选项，要求选项与你计算的结果相差在 1% 以内，否则选择选项 A: 其他选项均不正确。
All other options are incorrect
0.455
 0.500
0.667
0.900
0.917
1.00
1.75
1.86
2.00
3.00
3.33
4.33
其他选项均不正确
0.455
 0.500
0.667
0.900
0.917
1.00
1.75
1.86
2.00
3.00
3.33
4.33
Solving this problem requires determining the structure changed in each optimization process, and then judging the purpose of the optimization process based on the structural change.

- For optimization process A:

Optimizing `ClC(C=C1)=CC=C1N2C3=NC=NC(NN4CCCCC4)=C3N=C2C5=C(Cl)C=C(Cl)C=C5` to `ClC(C=C1)=CC=C1N2C(C3=C(Cl)C=CC=C3)=NC4=C(N=CN=C42)N5CCC(NCC)(C(N)=O)CC5`. Replacing `[*]NN1CCCCC1` in the original structure with `O=C(N)C1(NCC)CCN([*])CC1`; replacing `ClC1=C([*])C=CC(Cl)=C1` with `[*]C1=C(C=CC=C1)Cl`.

For such structural changes, connecting a hydrophilic amide group and an amino group to the lipophilic piperidine ring, such an optimization process can improve the hydrophilicity of the compound. Therefore, the main purpose corresponding to optimization process A is 1. Reduce the lipophilicity of the compound.

<Checkpoint>[Optimization process A connects a hydrophilic amide group and an amino group to the lipophilic piperidine ring.](1)</Checkpoint>

<Checkpoint>[The main purpose corresponding to optimization process A is 1. Reduce the lipophilicity of the compound.](1)</Checkpoint>

- For optimization process B:

Optimizing `ClC1=CC=C(O[R])C(NC2=NC(C([O-])=O)=CS2)=C1` to `ClC1=CC=C(C([R])=CN2C3=NC(C([O-])=O)=CS3)C2=C1`, where the two adjacent substituents `ClC1=CC=C(O[R])C(N[*])=C1` of the benzene ring are replaced with an N-substituted indole ring `ClC1=CC=C(C([R])=CN2[*])C2=C1`.

Observing the original structure, it can be found that there is a five-membered intramolecular hydrogen bond between the two adjacent substituents `[*][NH][*]` and `[*]O[R]` of the benzene ring, which fixes the conformation of the molecule, which may be the active conformation of the molecule. Therefore, the optimization process replaces the relatively unstable five-membered ring hydrogen bond with an indole ring, fixing such an active conformation. Therefore, the main purpose corresponding to optimization process B is 3. Fix the molecular conformation as the active conformation.

<Checkpoint>[In optimization process B, the original structure can form a hydrogen bond to fix the conformation.](1)</Checkpoint>

<Checkpoint>[The main purpose corresponding to optimization process B is 3. Fix the molecular conformation as the active conformation.](1)</Checkpoint>

- For optimization process C:

Optimizing `CNC1=NN=C(C)C2=CC=CC=C21` to `CNC(C1=CC=CC=C1NC)=O`, where the phthalazine heterocycle `[*]C1=NN=C([*])C2=CC=CC=C21` is replaced with an ortho-disubstituted benzene ring `O=C([*])C1=CC=CC=C1N[*]`.

Observing the two substituents after optimization: the carbonyl group `[*]C(=O)[*]` and the amine group `[*][NH][*]`, it can be found that an intramolecular six-membered ring hydrogen bond can be formed, so that the conformation of phthalazine in the original structure can be maintained. At the same time, phthalazine is a non-drug-like structure, and replacing it with carbonyl and amine groups, which are more common in drugs, can enhance the drug-likeness. Therefore, the main purpose corresponding to optimization process C is 4. Maintain the conformation and improve drug-likeness.

<Checkpoint>[The carbonyl and amino groups in the new structure can form hydrogen bonds, so that the conformation of phthalazine in the original structure can be maintained.](1)</Checkpoint>

<Checkpoint>[The main purpose corresponding to optimization process C is 4. Maintain the conformation and improve drug-likeness.](1)</Checkpoint>

- For optimization process D:

Optimizing `OC(C(C)C1=CC(C(C2=CC=CC=C2)=O)=CC=C1)=O` to `OC(C(C)C1=CC(C(C2=CSC=C2)=O)=CC=C1)=O`, where the benzene ring `[*]C1=CC=CC=C1` is replaced with a thiophene ring `[*]C1=CSC=C1`.

The benzene ring and the thiophene ring are a pair of classic bioisosteres, and this replacement has no other obvious purpose. Therefore, the main purpose corresponding to optimization process D is 2. Bioisostere replacement.

<Checkpoint>[The benzene ring and the thiophene ring are a pair of classic bioisosteres, and this replacement has no other obvious purpose.](1)</Checkpoint>

<Checkpoint>[The main purpose corresponding to optimization process D is 2. Bioisostere replacement.](1)</Checkpoint>

- For optimization process E:

Optimizing `CCCCNC(NS(=O)(C1=CC=C(C=C1)C)=O)=O` to `CCCCNC(NS(=O)(C1=CC=C(C=C1)Cl)=O)=O`, where the p-toluenesulfonyl group `O=S(C1=CC=C(C=C1)C)([*])=O` is replaced with a p-chlorobenzenesulfonyl group `O=S(C1=CC=C(C=C1)Cl)([*])=O`.

The benzylic methyl group is easily oxidized and metabolized. Replacing the easily oxidized benzylic methyl group with chlorine can enhance the metabolic stability of the drug. Therefore, the main purpose corresponding to optimization process E is 5. Improve the metabolic stability of the drug.

<Checkpoint>[The benzylic methyl group is easily oxidized and metabolized.](1)</Checkpoint>

<Checkpoint>[The main purpose corresponding to optimization process E is 5. Improve the metabolic stability of the drug.](1)</Checkpoint>

- For optimization process F:

Optimizing `O=C(NC1=CC=C(Cl)C=C1C(NCC2CCCCC2)=O)C3=C4C=CC=CC4=CC=C3` to `O=C(NC1=CC=C(Cl)N=C1C(NCC2CCOCC2)=O)C3=C4C=CC=CC4=C(CS(C)=O)C=C3`, where the substituent `O=S(C)C[*]` is added, the benzene ring in `O=C([*])NC1=CC=C(Cl)C=C1C(N[*])=O` is replaced with a pyridine ring `O=C([*])NC1=CC=C(Cl)N=C1C(N[*])=O`, and the cyclohexyl group `[*]C1CCCCC1` is replaced with a tetrahydropyranyl group `[*]C1CCOCC1`.

The above three changes will enhance the hydrophilicity of the molecule and reduce the lipophilicity of the compound. Therefore, the main purpose corresponding to optimization process F is 1. Reduce the lipophilicity of the compound.

<Checkpoint>[The structural changes are 1. replacing the benzene ring with a pyridine ring, 2. replacing the cyclohexyl group with a tetrahydropyranyl group, 3. adding a sulfinyl group.](1)</Checkpoint>

<Checkpoint>[The main purpose corresponding to optimization process F is 1. Reduce the lipophilicity of the compound.](1)</Checkpoint>

Calculate the final value of $z$:

$$
z = \dfrac{1\times4\times5}{3+2+1}=\dfrac{20}{6}=3.33
$$

<Checkpoint>[$z =3.33$](1)</Checkpoint>
解决这道题目，需要判断每个优化过程中改变的结构，然后再根据结构的变化判断优化过程的目的。

- 对于优化过程 A：

将 `ClC(C=C1)=CC=C1N2C3=NC=NC(NN4CCCCC4)=C3N=C2C5=C(Cl)C=C(Cl)C=C5` 优化为 `ClC(C=C1)=CC=C1N2C(C3=C(Cl)C=CC=C3)=NC4=C(N=CN=C42)N5CCC(NCC)(C(N)=O)CC5`。将原始结构中的 `[*]NN1CCCCC1` 替换为 `O=C(N)C1(NCC)CCN([*])CC1`；将 `ClC1=C([*])C=CC(Cl)=C1` 替换为 `[*]C1=C(C=CC=C1)Cl`。

对于这样的结构变化，将亲脂性六氢吡啶环连上亲水性酰胺基和氨基，这样的优化过程可以提升化合物的亲水性，因此，优化过程 A 对应的主要目的是 1. 降低化合物亲脂性。

<Checkpoint>[优化过程 A 将亲脂性六氢吡啶环连上亲水性酰胺基和氨基。](1)</Checkpoint>

<Checkpoint>[优化过程 A 对应的主要目的是 1. 降低化合物亲脂性。](1)</Checkpoint>

- 对于优化过程 B：

将 `ClC1=CC=C(O[R])C(NC2=NC(C([O-])=O)=CS2)=C1` 优化为 `ClC1=CC=C(C([R])=CN2C3=NC(C([O-])=O)=CS3)C2=C1` ，其中将苯环的邻位两个取代基 `ClC1=CC=C(O[R])C(N[*])=C1` 替换为 N-取代的吲哚环 `ClC1=CC=C(C([R])=CN2[*])C2=C1`。

观察原始结构可以发现，其中存在苯环邻位两个取代基 `[*][NH][*]` 与 `[*]O[R]` 的五元环分子内氢键，其固定了分子的构象，这可能是分子的活性构象，故优化过程将相对不稳定的五元环氢键替换为吲哚环，固定了这样的活性构象，因此，优化过程 B 对应的主要目的是 3. 固定分子构象为活性构象。

<Checkpoint>[优化过程 B 中，原始结构可以形成氢键固定构象。](1)</Checkpoint>

<Checkpoint>[优化过程 B 对应的主要目的是 3. 固定分子构象为活性构象。](1)</Checkpoint>

- 对于优化过程 C:

将 `CNC1=NN=C(C)C2=CC=CC=C21` 优化为 `CNC(C1=CC=CC=C1NC)=O`，其中将酞嗪杂环 `[*]C1=NN=C([*])C2=CC=CC=C21` 替换为邻位二取代的苯环 `O=C([*])C1=CC=CC=C1N[*]`。

观察优化后的两个取代基：羰基 `[*]C(=O)[*]` 与胺基 `[*][NH][*]` 可以发现，其中可以生成分子内的六元环氢键，从而使得原本结构中酞嗪的构象得以保持，同时，酞嗪为不类药的结构，将其替换为药物中更常见的羰基与胺基，可以增强器类药性，因此，优化过程 C 对应的主要目的是 4. 不改变构象同时提升药物类药性。

<Checkpoint>[新结构中羰基和氨基可以形成氢键，使得原本结构中酞嗪的构象得以保持。](1)</Checkpoint>

<Checkpoint>[优化过程 C 对应的主要目的是 4. 不改变构象同时提升药物类药性。](1)</Checkpoint>

- 对于优化过程 D:

将 `OC(C(C)C1=CC(C(C2=CC=CC=C2)=O)=CC=C1)=O` 优化为 `OC(C(C)C1=CC(C(C2=CSC=C2)=O)=CC=C1)=O`，其中的苯环 `[*]C1=CC=CC=C1` 替换为噻吩环 `[*]C1=CSC=C1`。

苯环与噻吩环是一对经典的生物电子等排体，且该替换无其他的明显目的，因此，优化过程 D 对应的主要目的是 2. 生物电子等排体替换。

<Checkpoint>[苯环与噻吩环是一对经典的生物电子等排体，且该替换无其他的明显目的。](1)</Checkpoint>

<Checkpoint>[优化过程 D 对应的主要目的是 2. 生物电子等排体替换。](1)</Checkpoint>

- 对于优化过程 E:

将 `CCCCNC(NS(=O)(C1=CC=C(C=C1)C)=O)=O` 优化为 `CCCCNC(NS(=O)(C1=CC=C(C=C1)Cl)=O)=O`，其中的对甲苯磺酰基 `O=S(C1=CC=C(C=C1)C)([*])=O` 替换为对氯苯磺酰基 `O=S(C1=CC=C(C=C1)Cl)([*])=O`。

苄位甲基易被氧化代谢，将易被氧化的苄位甲基替换为氯，可以增强药物的代谢稳定性，因此，优化过程 E 对应的主要目的是 5. 提升药物代谢稳定性。

<Checkpoint>[苄位甲基易被氧化代谢。](1)</Checkpoint>

<Checkpoint>[优化过程 E 对应的主要目的是 5. 提升药物代谢稳定性。](1)</Checkpoint>

- 对于优化过程 F: 

将 `O=C(NC1=CC=C(Cl)C=C1C(NCC2CCCCC2)=O)C3=C4C=CC=CC4=CC=C3` 优化为 `O=C(NC1=CC=C(Cl)N=C1C(NCC2CCOCC2)=O)C3=C4C=CC=CC4=C(CS(C)=O)C=C3`，其中增加了取代基 `O=S(C)C[*]`，将 `O=C([*])NC1=CC=C(Cl)C=C1C(N[*])=O` 中的苯环替换为吡啶环 `O=C([*])NC1=CC=C(Cl)N=C1C(N[*])=O`，将环己基 `[*]C1CCCCC1` 替换为四氢吡喃基 `[*]C1CCOCC1`。

以上三处变化都将增强了分子的亲水性，降低化合物亲脂性，因此，优化过程 F 对应的主要目的是 1. 降低化合物亲脂性。

<Checkpoint>[结构变化是1.将苯环替换为吡啶环，2.将环己基替换为四氢吡喃基，3.添加亚砜基。](1)</Checkpoint>

<Checkpoint>[优化过程 F 对应的主要目的是 1. 降低化合物亲脂性。](1)</Checkpoint>

计算最终的 $z$ 的值：

$$
z = \dfrac{1\times4\times5}{3+2+1}=\dfrac{20}{6}=3.33
$$

<Checkpoint>[$z =3.33$](1)</Checkpoint>