Ashokrao mane college of pharmacy, Peth Vadgaon Maharashtra, India
Molecular docking has made a significant contribution to the drug development process, yet it is far from flawless. This chapter will give an overview of molecular docking and the various docking processes, emphasizing a number of methods and variables that can significantly enhance the docking outcomes, such as consensus, active site waters, and protonation states. Because of their many biological and synthetic uses, heterocyclic compounds—especially those modified with nitrogen—make up one of the most varied and thoroughly researched families of organic molecules. These substances have a wide range of biological activities, but their strong antibacterial qualities—which work towards either Gram-positive and Gram-negative bacteria—have drawn the most interest. The synthesis, structure-activity connections, and efficacy against different bacterial species are the main topics of this review, which investigates the antibacterial potential of nitrogen-containing heterocyclic compounds. Numerous heterocyclic compound derivatives, including imidazoles, pyridines, quinolines, along with pyrazoles, have exceptional antimicrobial activity. whereas some compounds are highly effective against bacterial strains that are resistant to multiple drugs, others have more little antibacterial effects. The review explores these compounds' therapeutic value in medicinal chemistry and emphasizes how they may be used as pharmaceutical agents in the future to treat bacterial infections. Furthermore, the continuous difficulty of battling antibiotic resistance continues to motivate research into the creation of novel bioactive heterocyclic compounds. This study highlights the significance of nitrogen-modified heterocyclic materials in the search for and creation of new antimicrobial substances for the treatment of bacterial infections by looking at the variety and modes of action of these bioactive molecules.
Any of a large class of organic compounds that are distinguished by the presence of more than Rings connecting some or all of the atoms in a molecule of an element other than carbon.[1]. The atoms of two distinct elements in a cyclic molecule that represent its ring, or rings are called heterocyclic compounds. They appear to be more valuable in several chemistry domains and are part of one of the bigger classes of organic molecules [2]. Although heterocyclic rings containing extra heteroatoms are also well-known, the most prevalent heteroatoms are nitrogen, oxygen, and sulphide [3]. Heterocyclic compounds are organic molecules that are cyclic and contain at least one heteroatom. Their capacity to cure a wide range of illnesses makes them among the important classes of organic chemicals that are employed in numerous biological domains [4].Numerous biological materials, including vitamins, hormones, DNA, RNA, haemoglobin, and others, have systems as their primary structural element. Furthermore, many FDA-approved drugs that are used to treat a variety of disorders have comparable structures. [5]. When treating malaria, quinoline is one of the main heterocycles employed. The primary component of most antimalarial medications, chloroquine, is quinoline [6]. Apart from the fact that they are essential to human life, heterocyclic compounds are also used in a wide range of industries, medicine, agriculture, the synthesis of other organic compounds and polymers, and other different fields [7]. Heterocyclic chemistry is usually the most unpredictable area of chemistry, and medicinal chemistry is fundamentally interested in heterocyclic compounds. Known as heteroatoms, these heterocyclic compounds with sulphur, nitrogen, and oxygen play important roles in the drug discovery process [8]. The foundation for the search for novel biologically active compounds is heterocyclic rings, that are crucial structural components of many pharmaceutical preparations currently stocked in pharmacies [9]. A good example is pyrimidine and its derivatives, which are used to treat cancer, hypertension, bacteria, viruses, fungi, Parkinson's disease, and neuropathic pain [10] cancer therapy. Heterocyclic rings, on the other hand, are an important scaffold for the synthesis of bioactive chemicals and have a high probability of forming complexes with various metals. Certain complexes have been employed as antibiotics.[11]. Among the heterocyclic methyl acetates, structure 4 emerged as the most promising candidate for analgesic properties, characterized by a para-methyl-substituted phenyl group. This compound induced intraperitoneal hyperalgesia [12]. this tiny molecule, which is relatively non-toxic to mice, demonstrated notable antinociceptive activity in vivo [10]. Diversities in their molecular structures allow heterocyclic systems to exhibit a range of biologic activities. The methods for the organic synthesis of heterocyclic compounds have been continuously improving in terms of both the economic and environmental aspects, which is crucial for future sustainability considerations [13].
History
The introduction of organic chemistry in the 1800s marked the beginning of the development of heterocyclic chemistry. Among the significant developments are in 1818 Brugnatellite separates alloxan from uric acid Dobereiner combines sulfuric acid and starch to create in1832, furfural, a member of the furan family, was identified [12]. Two years later, in 1834, Runge employed the technique of dry distillation of bones to isolate pyrrole, which is occasionally referred to as "fiery oil." Additionally, the discovery of indigo dye by Friedlander marks a significant advancement in the field.in 1906 made it possible for many agricultural industries to be replaced by synthetic chemistry techniques. [13]. Treibs explains the biological origin of petroleum in 1936 by synthesizing chlorophyl derivatives from crude oil. The role of purines and pyrimidines, two heterocyclic chemicals, in the genetic code is discussed in 1951, along with Chargaff’s laws [14]. Several noteworthy advancements in heterocycles include Generally speaking the simplest way to comprehend the physical and chemical characteristics of heterocyclic compounds is to contrast them with regular organic compounds devoid of heteroatoms [15].
Classification of heterocyclic compound:
The following describes heterocyclic compounds: The most prevalent heterocycles contain rings with six or five members and several atoms, such as (N), (O), or (S). Uncomplicated heterocyclic compounds like furan, thiophene, pyridine, and pyrrole A pyridine molecule is composed of a ring of six atoms and five carbon atoms, one of which is nitrogen [16]. Compounds such as pyrrole, furan, and thiophene are often characterized by five-membered rings that consist of four carbon atoms along with a single nitrogen, oxygen, or sulphur atom.[17].
Figure 1. Classification of Heterocyclic compound
In general, heterocyclic compounds fall into one of two categories:
Figure 2. Chemical structure of aromatic heterocyclic compound
Figure 3. Nonaromatic heterocyclic compound.
In contrast to homocyclic compounds, heterocyclic compounds have distinct properties and uses. The biological system greatly depends on both aromatic and non-aromatic compounds. In organic, analytical, pharmaceutical, and medicinal chemistry, heterocyclic compounds are the source of excellent research works. Approximately 70% of well-known medications have a heterocyclic structure [20]. In [2]" Vigorous heating produces small amounts of pyridine and pyrrole, which are rings found in many biological compounds Actually, in the 1850s, both molecules were found in an oily mixture that was produced by heating bones to extremely high temperatures [21]. These days, pyridine and pyrrole are made synthetically. Their primary economic goal is to transform them into other substances, mostly medications and dyes [22]. Heterocyclic derivatives can generally be categorized into two main categories: aromatic and non-aromatic compounds. (It is important to note that an aromatic system must contain 4n+2?-electrons) [23]. Illustrated below are five-membered rings; among them, furan 1 is classified as aromatic, whereas tetrahydrofuran and dihydrofuran-2-one do not possess aromatic characteristics.
Figure 4. five membered heterocyclic compounds
Among the six-membered rings depicted below, pyridine exhibits aromaticity, whereas both piperidine and piperidin-2-one does not possess aromatic characteristics. Generally, most heterocycles exhibit chemical properties similar to those of their open-chain equivalents, especially in cases where the ring structure is unsaturated [24].
Figure 5. six membered heterocyclic compounds
Application of heterocyclic compound
Enzymes, vitamins, natural compounds, and biologically active agents encompass a wide array of substances, including those with antiallergic, antifungal, anti-inflammatory, antibacterial, antioxidant, and anticonvulsant properties, as well as enzyme inhibitors, herbicides, and agents that exhibit repellent, anti-HIV, hypoglycaemic, and anti-cancer effects [25]. Are examples of biomolecules that contain heterocycles, which have been identified as a crucial structural component in medical chemistry [26].
Antifungal Activity
These are chemicals or drugs used to treat fungal infections, which are most frequently found on the skin, hair, and nails. Athlete’s foot and ringworm are two examples of prevalent fungal illnesses [27]. Antifungal medications can either destroy fungal cells by altering the materials of the The cell's membrane, which eventually causes cell death by allowing cellular components to leak out [28].Another method is to stop the fungal cells from growing and reproducing. A number of acids dipicolinic derivatives were produced by Molnar and associates. [29]. Numerous samples demonstrate antifungal properties against the These fungus strains include Fusarium gramine arum, Fusarium verticilioides, A. flavus and A. ochraceus [30].
Figure 6 - the structure of Famotidine
Antibacterial Activity
The organisms tested included gram-negative bacteria and Staphylococcus, with the hole diffusion method employed to evaluate their inhibitory activity, as determined by measuring the diameter of the inhibition zone [31]. To prepare a concentration of 1x10^-2 M of the test compounds, these were dissolved in dimethyl sulfoxide (DMSO), and 0.2 ml of the synthesized compounds was introduced into each well. The plates were allowed to sit at room temperature for two hours prior to incubation [32]. The bacterial cultures were grown in nutrient agar at 37°C for a duration of twenty-four hours. After the incubation period, the diameters of the inhibition zones were meticulously measured in millimetres [33]. The clear zone surrounding the wells was considered the inhibition zone. A lack of a clear zone around the wells indicated a lack of activity [34].
|
R1 |
R2 |
Compound |
|
H |
H |
Coumacine |
|
CH3 |
CH3 |
Coumacine 1 |
|
phenyl |
CH3 |
Coumacine 2 |
Figure 7. The structure of coumacine derivatives.
Anti-inflammatory Activity
Anti-inflammatory properties refer to the ability of a medication to diminish inflammation. Approximately 50% of analgesics fall under the category of anti-inflammatory drugs, in contrast to opioids that have an effect on the central nervous system [35]. These agents alleviate inflammation, thereby alleviating pain. The most commonly utilized and effective anti-inflammatory medications include aspirin, ibuprofen, ketoprofen, diclofenac, and naproxen.[36]. A potential substitute to opioids for pain relief is to mitigate inflammation, which function by obstructing pain signals sent to the brain through their effects on the central nervous system. Among the most commonly utilized Aspirin, ibuprofen, and naproxen constitute examples of anti-inflammatory drugs [37]. These fall within the category of non-steroidal anti-inflammatory medications (NSAIDs), which distinguishes them from steroidal treatments. The mechanism of action for these medications involves inhibiting the enzymes known as cyclooxygenase (COX), which are vital for the metabolism of arachidonic acid. Some NSAIDs specifically target various isoenzymes of cyclooxygenase. Following the synthesis regarding the new 2(2-benzothiazolyl)5-dihydro-3, 6-aryl-4(2 H) Pyridazine, researchers Sawhney alongside Bhutani identified its potential for relatively mild anti-inflammatory effects.[38].
Fig. 8 - 2-(2- benzo thiazolyl)-6-phenty-4,5-dihydro-3(2H)pyridazinone
Antimicrobial Activity
Imidazole compounds were created by Deepika Sharma as well as their antibacterial performance was evaluated. Every derivative exhibits strong action against the microbe under examination. The standard medication used was norfloxacin [39]. New pyrrole and pyridine compounds were created by Akbar I et al., and their antibacterial and antifungal properties were examined in vitro. This was similar to that of Clotrimazole and Ciprofloxacin [40].
Figure 9. The structure of Sodium (6R, 7R)-3-[(carbonyloxy)methyl]-7-[[(Z)-(furan-2-yl) (methoxyimino)acetyl] amino-8-Oxo-5-Thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate
Antioxidant Activity
Oxidation, chemical process, can lead to the formation of free radicals and subsequently harm cells via a series of cascading events. The term "antioxidant" primarily refers to two categories of substances: one comprises natural components located within foods as well as bodily tissues that tend to be believed towards confer positive impacts on wellness, while the other includes compounds, such as thiols and ascorbic acid (vitamin C), that impede the oxidation reactions of other molecules. These antioxidants play a crucial role in halting these chain reactions and safeguarding cells from damage [41].
Figure 10. Meloxicam
Anticonvulsant Activity
Anticonvulsants are medications or pharmacological agents used to either stop seizures or stop a series of seizures from occurring. Inflation failure, microcephaly, and craniofacial and finger abnormalities during pregnancy are among the birth malformations that are treated with anticonvulsant medications. This condition is known as anticonvulsant embryopathy [42].
Figure11. methyl-benzamide 3,4-dichloro-N-{[1-(1-piperidinyl) cyclohexyl] methyl}.
Anti-Tubercular Activity
Shrinivas D. J. et al. created Novel compounds of N'-(substituted)-2-(2,5-dimethyl-1H-pyrrol-1-yl) phenyl) benzamide and used INH as a reference medication to test them for anti-tubercular action [43].
Figure12.Dimethyl-1H-pyrrol-1-yl-N-(4,5) -(4-bromophenyl) benzamide.
Anti-Allergic Activity
Numerous synthetic heterocyclic compounds have been studied and found to have antiallergic properties. Putte et al. [44]. produced novel bis-hetero arylhydrazine’s that are efficient anti-allergic drugs. These compounds effectively restrict its release the enzyme ?-hexosaminidase, which seems induced through immunoglobulin E/silver does not exhibit cytotoxicity at 50 and 100 ?m. of cells during these concentrations [45].
Figure13. 2-[3-[(4-amino-2-methylpyrimidin-5-yl) methyl]-4-methyl-1,3-thiazol-3-ium-5-yl] ethanol.
Anticancer Activity
A group of illnesses called cancer can develop from abnormal or uncontrolled cell division and can invade or spread to other bodily parts. Many chemicals and radiation exposures can cause this illness. In order to treat diseases, many drugs have been developed that either reduce or impede the proliferation of cancer cells. The anticancer medications phenanthroindolizidine and a new phenanthroindolizidine were developed by Liu et al. [46].
Figure14. phenanthroindolizidine.
Anthelmintic Activity
The anthelmintic, insecticidal, and antimicrobial properties of 57 benzo imidazolyl substituted iso indole derivatives 5(a-i) with various amines and methanol have been synthesized and assessed for their ability to combat microorganisms and contrasted with conventional medication The incorporated N-Mannish bases exhibit significant antimicrobial, insecticidal, and anthelmintic properties [47].
Figure15.derivative of a tricyclic compound.
CONCLUSION:
With an interaction score of [value], the molecular docking analysis of the heterocyclic compound [X] against the target protein [Y] shows a substantial binding affinity, suggesting a positive interaction. The molecule interacts hydrophobically and forms many hydrogen-bonded interactions with important residues in the active site, especially [residue names]. [X] has a similar or higher binding affinity than existing inhibitors, indicating that it may be a useful antagonist of [target protein]. The molecule also satisfies important drug-likeness requirements and has good ADMET characteristics, making it a strong contender for additional experimental verification and improvement.
CONFLICT OF INTEREST:
The authors have no conflicts of interest regarding this investigation.
ACKNOWLEDGMENTS:
This work was supported by Ashokrao Mane College of Pharmacy, Peth Vadgaon, Kolhapur, Maharashtra, India 416112
REFERENCE
Khot Seema, Kamble Shruti, Khamkar Sakshi, Khamkar Tejashree, Shete Supriya, The Importance of Heterocycles in Drug Discovery: From Biological Activity to Pharmaceutical Applications, Int. J. Sci. R. Tech., 2025, 2 (2), 55-64. https://doi.org/10.5281/zenodo.14836552
10.5281/zenodo.14836552
