INTRODUCTION:

Antimicrobial resistance (AMR) seriously threatens the world's healthcare system. It was formerly thought to be a far-off menace, but as more illnesses become resistant to current medicines, it has become a significant obstacle. The widespread use of antimicrobials, microorganisms' innate capacity for adaptation and the development of resistance mechanisms are the leading causes of this phenomenon. AMR has far-reaching effects, including higher rates of illness and death, longer hospital stays, and rising healthcare expenses¹. The context of AMR makes clear the connections between the health of humans and animals and the environment. Overuse of antibiotics in human treatment can develop resistant bacteria, which can then infect animals directly or through the food chain. Therapy for diseases may become more difficult to cure if these resistant germs re-enter the human population. Furthermore, resistant microbes may proliferate due to environmental pollution with antibiotic residues^2-3. To effectively address this complex issue, a One Health strategy is essential (Fig. 1). To tackle AMR, healthcare professionals, veterinarians, and environmental scientists must collaborate to design and execute effective methods^4-5.

Figure 1: One Health: Connecting people, animals, and the environment

There has never been a greater need to find innovative antimicrobial drugs. There is now a serious vacuum in the treatment arsenal due to the substantial decline in the pipeline for novel antibiotics in recent decades. In an attempt to tackle this urgent problem, scientists are now investigating a variety of chemical scaffolds that may be antibacterial. Chromenes stand out among these as a potentially helpful class of substances. Benzene and pyran rings are united to form a class of heterocyclic compounds called chromophores or benzopyrans. Their structural variety, which results from differences in ring size and substitution patterns, provides many opportunities for drug development^6-7. Numerous manufactured and natural products have been found to include the core chromene scaffold, which is known to display a wide spectrum of biological activity. In contrast to other heterocyclic systems, the antibacterial potential of chromenes has not received as much attention. There is a clear research deficit in thoroughly assessing chromenes as antibacterial agents. Although certain chromene derivatives have been shown to exhibit antibacterial characteristics in isolated experiments, their structure-activity correlations, modes of action, and effectiveness have not been thoroughly investigated. By offering a thorough analysis of chromenes as antimicrobial agents, including their chemistry, biological activity, and potential as lead compounds for the creation of new antimicrobials, this study seeks to close this knowledge gap. This review aims to investigate chromenes' potential as antibacterial agents thoroughly. This effort aims to find important structural characteristics linked to antimicrobial efficacy and establish structure-activity connections by exploring the chemistry and synthesis of derivatives of chromene^8-9. Moreover, the methods by which chromenes carry out their antimicrobial actions will be clarified, offering an understanding of their mode of action. The antibacterial activity of chromenes against a wide range of pathogens will be assessed, both in vitro and in vivo, to determine their therapeutic potential. Furthermore, these compounds' safety and toxicity profiles will be investigated to pinpoint potential additional research and development candidates. This review aims to add to the expanding body of information on chromenes and their potential as a novel class of antibacterial agents by addressing these important elements^11-12.

Chemistry And Synthesis of Chromenes:

The benzene ring fused to the pyran ring, or chromene scaffold, provides an adaptable foundation for structural diversity and chemical manipulation. As a result, several artificial methods have been used to obtain chromene derivatives with different substitution patterns. These methods include both traditional organic transformations and newer techniques, making it possible to synthesize chromene core with various ring diameters and functions (Fig. 2). The understanding of structure-activity relationships (SAR) is fundamental to studying chromophore chemistry¹³. Scientists can discern crucial structural factors that impact biological activity through methodical modifications of the chromene scaffold. These investigations offer priceless information in maximizing compounds' pharmacokinetic, selectivity, and potency. Antimicrobial activity, for example, has been demonstrated to be strongly influenced by the substitution pattern on the benzene ring, the kind of pyran ring (dihydro- or tetrahydro-), and the presence of functional groups at different places, even with the tremendous advancements in chromene production, difficulties still exist^14-15

Figure 2: Synthesis methods for Chromenes

Research is ongoing to produce scalable and effective synthesis methods for complex chromene derivatives. Moreover, it is imperative to investigate new synthetic approaches to get various chromene scaffolds to broaden the chemical space and discover novel antimicrobial agents. Moreover, because stereochemistry has a strong effect on biological activity, including it in chromene synthesis is a challenging task. To tackle these obstacles, novel catalysts, reagents, and reaction conditions must be used. The subject of chromene chemistry and synthesis is active and constantly changing^15-18.

Figure 3: Synthesis of Chromenes

Researchers may fully utilize this heterocyclic scaffold in the quest for new antimicrobial drugs by perfecting the technique of chromene synthesis and comprehending the structure-activity correlations dictating their biological effects. To investigate microwave irradiation, a quick and effective method to synthesize chromenes, a family of compounds with interesting chemical and biological uses. The drawbacks of conventional chromene synthesis and the benefits of microwave-assisted techniques. Subsequently, they explore the latest findings of chromenes that possess anti-microbial, anti-cancer, and insecticidal characteristics, emphasizing the possibility of using this method to synthesize novel pharmaceuticals^16-18. Lastly, the paper advances more environmentally friendly microwave-based chromene synthesis techniques (Fig. 3).

Antimicrobial Activity of Chromenes:

Chromenes have demonstrated promising antibacterial activities against a variety of microbes. Their effectiveness against fungus, bacteria, and occasionally viruses has drawn much interest. The minimum inhibitory concentration (MIC), which denotes the lowest concentration of a substance that inhibits a microorganism's observable development, is a crucial measure in assessing the efficacy of antibiotics. Lower MIC values indicate greater antibacterial effectiveness. Studies that compare chromenes to conventional antibiotics have yielded important information about their potential as antibacterial agents. Certain chromene compounds have shown equivalent or even more antibacterial activity than known antibiotics, while others have shown weaker results^19-20. These differences can be explained by variables like the target microbe, the particular chromene structure, and the experiment's setup. To maximize the therapeutic potential of chromenes, it is crucial to comprehend the processes behind their antibacterial effect. Numerous mechanisms of action have been suggested, such as DNA replication suppression, loss of cell membrane integrity, interference with protein synthesis, and inhibition of cell wall formation. Nevertheless, many chromene derivatives still lack clear mechanisms of action. More investigation is required to broaden the structural variety of these compounds and examine their action against a more diverse array of microbes to realize the antimicrobial potential of chromenes21-22 fully. Clarifying the mechanisms of action will also make it easier to logically develop new chromene derivatives with improved antibacterial capabilities. By focusing on these important areas, scientists can help battle the rising problem of antimicrobial resistance by developing efficient agents based on chromene^23-24.

Mechanisms of Antimicrobial Action:

To synthesize novel medications and battle antibiotic resistance, it is essential to comprehend the processes by which antimicrobial medicines work. Numerous microbial cell targets have been used in therapeutic interventions^24-25.

Figure 4: Antimicrobial therapy strategies

Figure 4 describes the different mechanisms of action that different classes of antimicrobials use to inhibit the growth of bacteria selectively. Antimicrobials can interfere with the synthesis of the cell wall by interfering with the transpeptidation process. For example, penicillin and cephalosporins inhibit cell wall synthesis by interfering with the transpeptidation mechanism. They can also interfere with the integrity of the cell membrane, as polymyxins disrupt the cell membrane by binding to the lipopolysaccharides in Gram-negative bacteria²⁶. Several classes of antibiotics have been structured to inhibit protein synthesis. Aminoglycosides and tetracyclines function through binding to the 30S ribosomal subunit, while macrolides and chloramphenicol interact with the 50S ribosomal subunit, thus inhibiting the process of protein synthesis. Certain antibiotics, like fluoroquinolones and revamping, target the synthesis of nucleic acids. Fluoroquinolones prevent DNA replication by interfering with DNA gyrase and topoisomerase IV, while revamping interferes with RNA synthesis by acting on RNA polymerase. Metronidazole affects DNA directly by producing toxic metabolites that cause damage to the DNA structure. Ultimately, they function by interrupting the synthesis of folic acid. This is an important pathway for bacterial proliferation. Sulphonamides act by competing with PABA, a precursor in folic acid biosynthesis. Trimethoprim inhibits dihydrofolate reductase, an essential enzyme in the folic acid synthesis pathway^26-27. By attacking these critical cellular processes, antimicrobial drugs can effectively curb the reproduction of bacteria and allow for the destruction of bacteria. It is noteworthy that the exact mechanism could vary depending on the type of drug and the strain of bacteria^28-29.

a) Inhibition of cell wall synthesis:

Peptidoglycan makes up most of the bacterial cell wall, an essential component that gives the cell form and protection. Numerous antibiotics target this vital element. Penicillin and cephalosporins are examples of beta-lactam antibiotics that block the latter steps of peptidoglycan production, causing cell lysis. Some classes, such as bacitracin and vancomycin, obstruct the early phases of constructing cell walls. These substances successfully stop bacterial growth and multiplication by upsetting this vital structure. Chromene derivatives have been proven to inhibit the cell wall biosynthesis of bacteria. The cell wall provides indispensable strength, a rigid and protective feature of bacteria. Therefore, interference in synthesizing this crucial structure renders the bacterial cell wall prone to lysis, leading to the cell's death. Transpeptidation is critical in synthesizing cell walls, where peptidoglycan layers cross-link. Chromene derivatives may bind to transpeptidase enzymes and thus prevent cross-linking, reducing the structural cohesion of the cell wall. Inhibition of lipid biosynthesis: Some chromene derivatives can inhibit the biosynthesis of lipids, which are essential components of the cell wall of the bacterial membrane. The disruption of lipid biosynthesis by chromene compounds may disrupt the structural integrity of the cell membrane and, therefore, result in cell death. Some metal ions are essential for bacteria's proliferation and cell wall biosynthesis^30-31. Chromene compounds can chelate these metal ions. Through the chelation of such essential metal ions, chromene compounds can inhibit different enzymatic steps vital in cell wall biosynthesis.

b) Interference with protein synthesis:

Protein synthesis is one basic biological function necessary for both growth and survival. Antibiotics can specifically target this process by attaching to the bacterial ribosome, the cellular machinery in charge of producing proteins. Antibiotics such as macrolides, tetracyclines, and aminoglycosides can obstruct the production of proteins. These medications attach to various ribosome locations, blocking the start or elongation of proteins and ultimately causing cell death. Chromene derivatives have been shown to inhibit bacterial cell wall synthesis, a critical step in the survival of bacterial organisms. These compounds are poised to interfere with numerous stages of cell wall synthesis: transpeptidation, lipid biosynthesis, and the chelation of metal ions. By interfering with these important processes, chromene derivatives can weaken the integrity of the bacterial organism's cell wall, ultimately leading to cell lysis and death. Furthermore, chromene derivatives can inhibit bacterial protein synthesis. They might act by binding to ribosomes, inhibiting mRNA translation, or interfering with the function of aminoacyl-tRNA synthetase. By inhibiting protein synthesis, chromene derivatives could successfully eliminate bacterial cells by preventing the expression of essential proteins. These mechanisms of action underscore the promise of chromene derivatives as innovative antimicrobial agents. Further investigations are required to give a clearer illustration of their specific mode of action and to enhance their therapeutic efficacy^29-31.

c) Disruption of cell membrane integrity:

The cell membrane is one essential barrier that keeps a cell isolated from its surroundings. Cell lysis and death can result from antimicrobial agents that compromise the integrity of the membrane. For example, phospholipids in Gram-negative bacteria's outer membrane interact with polymyxins, causing cell breakdown and leakage. Certain antimicrobial peptides also work against bacteria by producing holes in their membranes. The chromene derivatives have been found to compromise the structural integrity of cell bacterial membranes. This essential structure manages the transport of nutrient and metabolic waste commodities crucial for bacterial survival. Therefore, the chromatin compounds could cause cell apoptosis by compromising the membrane integrity^24-26. Several mechanisms have been proposed to explain this membrane disruptive event. One plausible mechanism is that chromene compounds promote lipid peroxidation, a biochemical reaction that causes damage to the lipid components of the membrane. Moreover, they could also affect the electrochemical gradient across the membrane, commonly known as the membrane potential, which plays a crucial role in a wide range of cellular activities. Lastly, some of these chromene compounds can make holes in the membrane, hence allowing the loss of vital cellular products. Chromene derivatives exert a promising action for combatting antibiotic-resistant infections through their specific targeting of the bacterial cell membrane. More research is needed to fully understand the mechanisms involved in membrane disruption and further improve the therapeutic potential of these compounds^30-33.

d) Inhibition of DNA Replication:

DNA replication is necessary for cell division and proliferation. Antimicrobial drugs that obstruct DNA replication can efficiently suppress microbial growth. Quinolones, like ciprofloxacin, prevent DNA gyrase from working, an enzyme needed for DNA replication and repair. This results in cell death and damage to DNA. Certain substances, including nitrofurantoin, can directly harm DNA, resulting in cellular death.

Figure 5: Inhibition of DNA damage repair by oncometabolite

Figure 5 illustrates the consequences of histone demethylation on the repair mechanisms occurring due to DNA damage. Under physiological conditions, the KDM4B-catalyzed demethylation of histones is responsible for recruiting DNA repair proteins such as ATM and Tip60 to the locus of DNA injury. It thus enables the effective performance of homology-dependent repair of the concerned DNA. However, in the case of an oncometabolite, KDM4B histone demethylation function is severely impaired. Thus, the DNA repair proteins are not recruited to the site of damage. This leads to the accumulation of unresolved DNA lesions, which fosters genomic instability and promotes tumorigenesis. Thus, the figure highlights the importance of histone demethylation in DNA damage repair. It further explains how its inhibition can lead to the failure of DNA repair mechanisms and the eventual development of cancers ^31-33.

e) Other Potential Mechanisms:

Antimicrobial drugs can act via several other pathways besides the well-known targets of DNA replication, cell wall formation, protein synthesis, and cell membrane integrity. Some substances' distinctive qualities and broad-spectrum action are frequently attributed to these alternate routes. An example of this process is the presence of antioxidants. Antioxidant qualities are frequently linked to defence against oxidative damage in host cells, but they can also support antimicrobial actions. Reactive oxygen species (ROS) can harm microbial cells, which is why oxidative stress is essential to the pathophysiology of many infectious illnesses. Antioxidant-capable compounds can neutralize these dangerous chemicals, which stops microbe development. Interference with metabolic processes represents another possible approach. For life and development, microorganisms need particular nutrients and metabolic activities. These pathways can be the focus of antimicrobial medicines, which work by blocking important enzymes or reducing vital metabolites. Sulphonamides, for instance, block the synthesis of folate, which is an essential step in synthesizing nucleic acids. Certain antimicrobial substances can also alter the immune response. These substances could boost immunity to fight infection more successfully or reduce overreactions to inflammation. These substances can indirectly support antibacterial action by affecting the host's defensive systems. It is essential to remember that many antimicrobial medicines have intricate and varied modes of action. Often, the whole antimicrobial action involves several targets and pathways. Comprehending these multifaceted pathways is vital to formulating innovative antimicrobial tactics and surmounting the obstacles presented by antibiotic resistance. Researchers can find new targets for developing antimicrobial drugs and increase the range of treatment choices available to treat infectious illnesses by investigating these different pathways^21-25.

Efficacy Studies:

Chromene derivatives have shown remarkable antimicrobial efficiency against various microorganisms, including bacteria, fungi, and viruses. Various in vitro studies have been conducted to evaluate their pharmacological activities. Minimum Inhibitory Concentration: The MIC is the most popular laboratory technique used to determine the minimum concentration of a pharmaceutical agent that inhibits the visible growth of a bacterium³⁵. The values of MIC for chromene derivatives were in the micromolar range against a range of bacterial species, including both Gram-positive and Gram-negative bacteria. Some studies have shown MIC values as low as 0.007 µg/mL for various chromene derivatives. Time-kill curves are a methodological approach to assessing antimicrobial agents' bactericidal or bacteriostatic properties. Chromene compounds have been found to exhibit both bactericidal and bacteriostatic activities, depending on the specific compound studied and the strain of bacteria tested³⁶. Several studies have reported rapid kinetics dramatically reducing bacterial numbers within hours after drug exposure. PAE describes the persistence of the inhibition of bacterial growth even after the drug concentrations drop below quantifiable levels from its previous exposure.7 Chromene derivatives have been reported to display a PAE against certain bacterial strains, suggesting an extended antimicrobial activity^35-36.

Although in vitro studies provide crucial information about the antimicrobial efficacy of chromene derivatives, in vivo studies are essential to assess their efficacy in the treatment of infections. Several different models of infection in animals have been used to assess the therapeutic potential of chromene derivatives. Chromene compounds have been tested in various animal models of bacterial infection, including those mimicking cutaneous, wound, and systemic infections. In these studies, chromene derivatives were significantly therapeutically effective, reducing the bacterial burden and increasing survival rates. Chromene compounds have also been tested in animal models of invasive fungal diseases like candidiasis. In these studies, chromene derivatives have demonstrated the ability to inhibit pathogens, diminishing fungal load and enhancing clinical effects. Summarily, the currently available in vitro and in vivo evidence suggests that chromene compounds possess great promise as antimicrobial agents. Further research is needed to refine their pharmacological characteristics and to allow them to be developed into effective clinical therapeutics^36-38.

Toxicity And Safety:

Although chromene derivatives hold much promise as potential antimicrobial agents, their possible toxicity and related safety issues must be fully explored. Although many studies have established that compounds belonging to this class are active against numerous microorganisms, little is known about their chronic toxicology and side effects³⁹. Other studies have shown that some chromene derivatives exhibit cytotoxic activity, especially when the dose is high. This suggests an urgent need to strictly optimize the dosages and formulations to minimize potential adverse effects. It is also important to study their activities on normal human cells and tissues to ascertain whether they could indeed be considered safe for therapeutic uses. In response to these concerns, researchers are vigorously investigating the structure-activity relationships of chromene derivatives. Through modifications to the chemical architecture of these compounds, it is possible that their antimicrobial activity could be enhanced while their toxicity is decreased. Finally, further research into controlled targeted drug delivery systems may minimize systemic exposure and thereby reduce the risk of side effects. Although the antimicrobial potential of chromene derivatives has tremendous promise in their use as antimicrobial agents, further research is needed to elucidate their safety profiles fully. Addressing their potential toxicity and formulating safe and efficacious preparations for these compounds may effectively solve this growing problem of antibiotic resistance^40-41.

The prospective utility of chromene derivatives as antimicrobial agents is considerable, especially in light of the rising prevalence of antibiotic resistance. Nonetheless, several obstacles hinder the complete realization of their therapeutic capabilities. A comprehensive understanding of the SAR of chromene derivatives is imperative for developing more efficacious and selective antimicrobials. Systematic alterations to the chemical structure of these compounds may facilitate the enhancement of their antimicrobial efficacy while concurrently mitigating adverse effects. While in vitro investigations have provided significant insights into the antimicrobial efficacy of chromene derivatives, it is crucial to assess their effectiveness and safety in animal infection models through in vivo studies, thereby discerning optimal dosing regimens and potential side effects. Developing appropriate formulations and delivery systems is vital to ensure the stability and bioavailability of chromene derivatives, along with their targeted delivery to the infection site, which is essential for achieving enhanced therapeutic efficacy with diminished systemic toxicity. Investigating the mechanisms by which bacteria develop resistance to chromene derivatives is equally critical^41-42. A thorough understanding of these resistance mechanisms can inform the design of strategies to prevent or overcome such resistance. Employing chromene derivatives in conjunction with other antimicrobial agents may enhance efficacy and avert the onset of resistance. The synergistic effects achieved by combining various medications can inhibit resistance development and yield superior clinical outcomes. chromene derivatives constitute a promising category of antimicrobial agents with potential applications in addressing the escalating issue of antibiotic resistance. By advancing research into their therapeutic potential and addressing existing challenges, scientists can devise novel and effective treatments for various infectious diseases^43-44.

FUTURE PERSPECTIVES:

One of the prime fields of potential application of chromene derivatives is as antimicrobial agents. Another key research topic is the synthesis of novel chromene derivatives that have increased antimicrobial activity with reduced toxicity. Scientists can improve their pharmacological properties through careful chemical engineering of their structure to target specific microorganisms while limiting side effects. This factor also includes the development of effective drug delivery systems⁴⁵. It is well known that such delivery systems can successfully improve bioavailability, accurately guide the pharmacological agent toward the locus of infection, and reduce systemic toxicity. Viable delivery modalities include nanoparticle-based delivery, liposomal encapsulation, and prodrug methodologies. Using effective drug delivery systems, researchers may fine-tune chromene derivatives' pharmacokinetic and pharmacodynamic attributes toward improved therapeutic outcomes. An integral part of the design of strong antimicrobial agents is understanding how bacteria achieve resistance. Like other antimicrobial agents, chromene derivatives may face the barrier of developing resistance. By studying the molecular mechanisms underpinning resistance, scientists can strategize ways to overcome resistance and expand the use of these compounds in clinical settings. Another quite promising approach to preventing the development of resistance is combination therapy, where chromene derivatives are combined with other antimicrobials⁴⁶. Combining drugs with different mechanisms of action can significantly reduce the opportunity for resistance to develop. Synergistic interactions of different drugs can enhance their therapeutic effects and broaden their spectrum of activity. To further develop the therapeutic use of chromene derivatives, extensive pharmacokinetic and pharmacodynamic studies are required. Such studies can provide invaluable information on drug absorption, distribution, metabolism, and excretion while helping to explain the relationship between drug concentration and therapy results. By determining such parameters, scientists can develop the most effective dosing regimens and limit the presence of harmful side effects^47-48.

CONCLUSION:

Chromene derivatives have emerged as a promising class of antimicrobial agents with the potential to address the growing threat of antibiotic resistance. Their diverse mechanisms of action, including inhibition of cell wall synthesis, disruption of protein synthesis, and damage to cell membrane integrity, offer a broad spectrum of antimicrobial activity^49-50. However, several challenges must be overcome to fully realize their therapeutic potential. Future research should focus on optimizing chromene structures for enhanced efficacy, minimizing toxicity, and developing innovative drug delivery systems. Additionally, collaborative efforts involving chemists, biologists, and clinicians are essential to accelerate the development of chromene-based therapeutics. By addressing these challenges, chromene derivatives may be valuable in the ongoing battle against infectious diseases^51-53.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

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Received on 29.11.2024 Revised on 17.02.2025

Accepted on 22.04.2025 Published on 19.06.2025

Available online from June 23, 2025

Asian J. Research Chem.2025; 18(3):185-193.

DOI: 10.52711/0974-4150.2025.00030

This work is licensed under a Creative Commons Attribution-Non Commercial-Share Alike 4.0 International License. Creative Commons License.