Heterocyclic compounds in Lead Optimisation

Heterocyclic compounds are a diverse class of molecules that play an important role in drug discovery. Heterocycles are defined as molecules that contain one or more atoms other than carbon in their ring structure. The most common heteroatoms found in heterocycles are nitrogen, oxygen, and sulfur.

Heterocyclic compounds have a number of properties that make them attractive for drug discovery. First, heterocyclic compounds are often more potent and selective than their aliphatic counterparts. This is because heterocyclic atoms can interact with the target protein in a variety of ways, including through hydrogen bonding, pi-stacking, and electrostatic interactions. Second, heterocyclic compounds often have improved physicochemical properties, such as solubility and permeability. This makes them more likely to be absorbed and distributed throughout the body. Third, heterocyclic compounds often have reduced toxicity. This is because heterocyclic atoms can help to reduce the interaction of the drug with off-target proteins.

As a result of these properties, heterocyclic compounds are commonly used in lead optimization. Lead optimization is the process of identifying compounds that have the potential to be developed into safe and effective drugs. Heterocyclic compounds are often used in lead optimization because they can provide a number of benefits, including increased potency, selectivity, improved physicochemical properties, and reduced toxicity.

There are a variety of different heterocyclic groups that can be used in lead optimization. Some of the most common include:

• Aromatic heterocycles, such as pyridine, pyrimidine, and thiophene
• Aliphatic heterocycles, such as piperidine, morpholine, and imidazole
• Heterocyclic rings with multiple heteroatoms, such as quinoline and isoquinoline

The choice of the heterocyclic group will depend on the target protein and the desired properties of the drug. For example, aromatic heterocycles are often used for their increased potency and selectivity, while aliphatic heterocycles are often used for their improved physicochemical properties.

Heterocyclic compounds are an important tool in lead optimization. They can provide a number of benefits that can help to improve the chances of developing a safe and effective drug.

Here are some examples of drugs that contain heterocyclic groups:

Nitrogen-containing heterocyclic compounds are not only present as the backbone in several biologically active natural products used as traditional medications or approved prescribed drugs, but some of their synthetic derivatives in different sizes, nowadays are prescribed and market purchasable drugs. The most famous are diazepam, isoniazid, chlorpromazine, metronidazole, barbituric acid, captopril, chloroquinine, azidothymidine and anti-pyrine. Furthermore, most of the vitamins, nucleic acid, enzymes, co-enzymes, hormones, and alkaloids contain N-based heterocycles as scaffolds

These are just a few examples of the many drugs that contain heterocyclic groups. Heterocyclic compounds are an important tool in drug discovery and play a vital role in the development of safe and effective medications.

References

• Heravi MM, Zadsirjan V. Prescribed drugs containing nitrogen heterocycles: an overview. RSC Adv. 2020 Dec 15;10(72):44247-44311. doi: 10.1039/d0ra09198g
• Jampilek J. Heterocycles in Medicinal Chemistry. Molecules. 2019 Oct 25;24(21):3839. doi: 10.3390/molecules24213839. 
• Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry" Molecules | Special Issue : Heterocycles in Medicinal Chemistry (mdpi.com)

These articles provide a comprehensive overview of the importance of heterocyclic compounds in drug discovery. They discuss the different types of heterocyclic compounds, their biological activities, and their potential as drug candidates. The articles also highlight some of the challenges associated with the development of heterocyclic drugs.

Halogens in Drug discovery

Halogens, which include elements such as fluorine, chlorine, bromine, and iodine, play a crucial role in lead optimization for achieving good logD values. LogD is a measure of the lipophilicity or hydrophobicity of a compound, and it is an essential parameter in drug discovery and development.

The incorporation of halogens into drug molecules can significantly impact their physicochemical properties, including lipophilicity, solubility, and bioavailability. Halogens are highly electronegative, which means that they can polarize the bonds they form with other atoms. This polarization effect can increase the lipophilicity of the molecule by making it more hydrophobic, which is desirable for drugs that need to cross cell membranes to reach their target.

In addition to increasing lipophilicity, halogens can also improve the metabolic stability of drug molecules. Halogens can act as electron-withdrawing groups, which can reduce the reactivity of other functional groups in the molecule. This reduced reactivity can prevent unwanted metabolic transformations, such as oxidation or hydrolysis, that can decrease the efficacy of the drug.

Furthermore, halogens can also enhance the potency of drug molecules by increasing their binding affinity to the target protein. Halogens can form strong hydrogen bonds with amino acid residues on the protein surface, which can improve the binding interactions between the drug and its target.

Overall, the strategic incorporation of halogens into drug molecules can greatly impact their pharmacological properties and improve their chances of success in lead optimization. By increasing lipophilicity, metabolic stability, and binding affinity, halogens can help researchers to develop more effective and potent drugs for a range of therapeutic applications.

There are many approved drugs that have been optimized using halogens to improve their activity and properties. Here are some examples:

1. Fluorouracil (5-FU) is a chemotherapy drug used to treat cancer. It contains a fluorine atom, which increases its lipophilicity and metabolic stability, improving its effectiveness.

2. Advair Diskus is a combination inhaler used to treat asthma and chronic obstructive pulmonary disease (COPD). It contains fluticasone propionate, which has a fluorine atom, and salmeterol, which has a chlorine atom. The halogens improve the lipophilicity and potency of the drugs, making them more effective at treating respiratory diseases.

3. Ciprofloxacin is a broad-spectrum antibiotic used to treat infections. It contains a fluorine atom, which enhances its antibacterial activity and improves its pharmacokinetic properties.

4. Zoloft (sertraline) is an antidepressant that contains a chlorine atom. The chlorine atom increases the drug's lipophilicity and metabolic stability, improving its effectiveness at treating depression.

These examples demonstrate the importance of halogens in optimizing drug molecules to improve their activity, potency, and pharmacokinetic properties. The strategic incorporation of halogens can help researchers to develop more effective drugs with fewer side effects, improving patient outcomes.

Chiral Alkyl Halides in Drug Discovery

Alkyl halides are a diverse class of compounds that have been used in a variety of applications, including drug discovery. Chiral alkyl halides, which have a chiral center, are of particular interest in drug discovery because they can offer a number of advantages over their achiral counterparts.

One advantage of chiral alkyl halides is that they can be more potent and selective than their achiral counterparts. This is because the chiral center can provide a point of chirality for interaction with a receptor, which can lead to improved binding affinity and selectivity.

Another advantage of chiral alkyl halides is that they can be more stable than their achiral counterparts. This is because the chiral center can provide a barrier to racemization, which is the process by which a chiral compound converts to its racemic (achiral) form.

Finally, chiral alkyl halides can be more easily manufactured than their achiral counterparts. This is because the chiral center can be introduced into the molecule using a variety of methods, including asymmetric synthesis and enzymatic resolution.

As a result of these advantages, chiral alkyl halides have been used in a number of successful drugs, including:

Halothane, an anesthetic

Clindamycin, an antibiotic

Pimecrolimus, an immunosuppressant

Sucralose, a sweetener

Chiral alkyl halides continue to be an important class of compounds in drug discovery, and they are likely to play a role in the development of new and improved drugs in the future.

References

1. "Chiral Alkyl Halides: Underexplored Motifs in Medicine." Frontiers in Pharmacology, vol. 7, 2016, doi:10.3389/fphar.2016.00279.

2. "A Unified and Desymmetric Approach to Chiral Tertiary Alkyl Halides." Journal of the American Chemical Society, vol. 144, no. 1, 2022, pp. 101–104., doi:10.1021/jacs.1c12404.

TriFluoro compounds in drug discovery

Trifluoro, which is a compound containing three fluorine atoms, has been widely used in lead optimization for drug discovery. There are several advantages and disadvantages to using trifluoro in this process.

Advantages:

1. Increased Lipophilicity: Trifluoro substitution can increase the lipophilicity of a drug molecule, which can improve its ability to cross cell membranes and reach its target. Lipophilicity is an important factor in determining the pharmacokinetic properties of a drug, such as its absorption, distribution, metabolism, and excretion.

2. Enhanced Metabolic Stability: The trifluoro group can increase the metabolic stability of a drug molecule by reducing the reactivity of other functional groups in the molecule. This can prevent unwanted metabolic transformations, such as oxidation or hydrolysis, which can decrease the efficacy of the drug.

3. Improved Binding Affinity: The trifluoro group can improve the binding affinity of a drug molecule to its target protein. The three fluorine atoms can form strong hydrogen bonds with amino acid residues on the protein surface, which can enhance the binding interactions between the drug and its target.

Disadvantages:

1. Toxicity: Trifluoro compounds can be toxic, especially if they are not metabolized properly. The toxic effects of trifluoro compounds can include liver and kidney damage, as well as central nervous system toxicity.

2. Reduced Solubility: Trifluoro substitution can reduce the solubility of a drug molecule, which can decrease its bioavailability. This can make it more difficult to achieve therapeutic concentrations of the drug in the body.

3. Synthetic Complexity: The synthesis of trifluoro compounds can be complex and challenging, which can increase the time and cost required for lead optimization.

In conclusion, trifluoro substitution can provide significant advantages in lead optimization for drug discovery, including increased lipophilicity, enhanced metabolic stability, and improved binding affinity. However, it is important to consider the potential disadvantages of trifluoro substitution, such as toxicity, reduced solubility, and synthetic complexity, when designing and optimizing drug molecules.

Just learned about #PROTACs, a promising new class of drugs that target #protein degradation! Exciting times in the world of drug discovery. 🧪💊 https://t.co/kc3jsYoms5

Just learned about #PROTACs, a promising new class of drugs that target #protein degradation! Exciting times in the world of drug discovery. 🧪💊 https://t.co/kc3jsYoms5

— Girinath G. Pillai (@giribio) May 1, 2023

from Twitter https://twitter.com/giribio

May 01, 2023 at 04:00AM