High Technology Letters ISSN NO : 1006-6748

Structural Alteration of Quinolone to Potentiate the Anti-Malarial Efficacy

by Docking Technique

Sudipta Modak1
Department of Pharmaceutical Sciences,
Jharkhand Rai University, Namkum, Ranchi, Jharkhand 834010, India

Syed Mohammad Abdullah 1

Department of Pharmaceutical Sciences,
Jharkhand Rai University, Namkum, Ranchi, Jharkhand 834010, India

Anjali Mishra*2
Faculty of Pharmacy,
Sarala Birla University, Mahilong, Ranchi, Jharkhand 835103, India

Shilpy Jha1
Department of Pharmaceutical Sciences,
Jharkhand Rai University, Namkum, Ranchi, Jharkhand 834010, India

Soham Koley1
Department of Pharmaceutical Sciences,
Jharkhand Rai University, Namkum, Ranchi, Jharkhand 834010, India

Shambhu Nath Saw1

Department of Pharmaceutical Sciences,
Jharkhand Rai University, Namkum, Ranchi, Jharkhand 834010, India

Abstract-

Quinolones, a kind of synthetic antimicrobial drug, have shown promise in treating malaria due to their ability to
inhibit the proliferation of Plasmodium species. However, difficulties with resistance and mediocre activity have limited
their clinical utility. In order to enhance the anti-malarial qualities of quinolones, structural modifications is required.
Our goals are to improve medication potency, decrease possible resistance, and improve Plasmodium selectivity by
altering functional groups and improving the quinolone core structure. Initial in vitro tests show that specific structural
alterations greatly boost anti-malarial efficacy against Plasmodium falciparum. These findings suggest that particular
structural changes to quinolones might greatly improve their therapeutic potential in malaria treatment. In order to
evaluate the safety and efficacy of these modified compounds in vivo.

Key words: Quinolones, Classification of Quinolones, in-vitro study, Derivatization of the fluoroquinolone, Docking
studies.

I. INTRODUCTION

A class of antibiotics known as fluoroquinolones have structural similarities with nalidixic acid and oxolinic acid.
Urinary tract infections have previously been treated clinically with both medicines. Nevertheless, even when
taken orally, fluoroquinolones, in contrast to nalidixic and oxolinic acids, reach serum quantities necessary for the
treatment of systemic infections. Many classes of antibiotics, notably the fluoroquinolones, block bacterial DNA
gyrase (topoisomerase II). There are two A and two B subunits in the enzyme. Although additional locations, such
as the B subunit and single-stranded DNA, have been discovered to be impacted by nalidixic acid and oxolinic
acid, the A-subunit appears to be their main target. However, novobiocin and coumermycin A1, two antibiotics
that are not structurally related to fluoroquinolones, inhibit the B-subunits. DNA gyrase is a crucial enzyme for

Volume 30, Issue 8, 2024 552 http://www.gjstx-e.cn/

High Technology Letters ISSN NO : 1006-6748

organisms like bacteria and organelles like mitochondria, which contain circular DNA, as it adds negative super
helical twists to double-stranded DNA1.
Generally, clinical malaria is caused by infection with four types of Plasmodium parasite. The most deadly
parasite, Plasmodium falciparum, exhibits a rising incidence of resistance to common medications like
chloroquine, the exact cause of which is unknown. A functioning mitochondria found in P. falciparum is
susceptible to a broad range of inhibitors. This parasite is fatal to mitochondrial inhibitors, such as medicines that
target 70S ribosomes. Since, the 70S ribosome inhibitors have been previously proposed by various researchers
to target the P. falciparum's mitochondria because of their unique toxicity that varies with time and oxygen
concentration. These factors make P. falciparum potentially vulnerable to such drugs most commonly known as
fluoroquinolones that inhibit typically DNA gyrase enzyme2.
Malaria continues to be a leading cause of death worldwide. The causing parasite can infect red blood cells and
the liver, where it multiplies, causing disease. Up to 80% of red blood cells (RBCs) may become parasitized and
may be killed in severe infections. It is well recognized that this enormous RBC cell death causes severe anemia,
obstructs the blood supply to main organs, especially the brain, and ultimately results in patient’s death.
Antimalarials drugs are given to prevent the growth of Plasmodium and the parasite that causes malaria, and are
intended to eradicate the parasites entirely. The selection of antimalarial medications is fairly broad. They can be
categorized based on their chemical makeup and function, or based on the many stages of the parasites they
impact3. So far, attempts to eliminate malaria through the use of these medicines and extremely potent residual
insecticides against mosquitoes have been unsuccessful. This is mostly because parasites are becoming more
resistant to medications and mosquitoes are becoming more resistant to insecticides. The elimination of malaria
continues to be one of the most difficult medical problems, for a variety of reasons, most importantly resistance
to anti-plasmodial drugs4.
The ongoing emergence of resistance to approved antimalarial medications, which is being documented in various
regions of the world, underscores the need for a more drastic solution to the malaria epidemic. As long as there is
proof of their safety and effectiveness, the World Health Organization's current recommendations for treating
malaria call for the combination of one antibiotic and one antimalarial. Therefore, it has been suggested that
combined therapy be utilized to help address this issue, and attempts are currently being made to identify suitable
combinations. First generation broad spectrum antibacterial agent particularly of quinolones group is
ciprofloxacin. It targets both the liver and blood parasite stages, and its potential for use as an antimalarial has
been considered to be good. Despite the possibility of high absorption and efficient erythrocyte penetration ability,
ciprofloxacin has not been recommended for use as a stand-alone antimalarial treatment. This is due to the fact
that the antiplasmodial activity of ciprofloxacin only manifests at an intolerable high dose and it is necessary to
obtain high serum concentration for adoption of an extended treatment regimen5.
1.1 Antimalarial Potential of Quinolones

There are various class of synthetic antimicrobial agents, quinolones are considered to be one of the most effective
entities in managing various infectious disorders particularly caused by bacteria. Quinolones are widely used as
broad spectrum antibiotic. It acts by inhibiting bacterial DNA gyrase and topoisomerase IV, enzymes critical for
DNA replication and repair6. This mechanism effectively disrupts bacterial cell division, leading to the death of
the bacteria. The quinolone class includes various generations, each with specific properties and spectrum of
activity. First-generation quinolones, like Nalidixic acid, have a narrower spectrum, mainly targeting Gram-
negative bacteria, while later generations, such as ciprofloxacin and levofloxacin, offer broader coverage against
both Gram-negative and Gram-positive bacteria7. Quinolones are used to treat a range of infections, including
urinary tract infections, respiratory infections, and certain types of infectious gastroenteritis. However, their use
is carefully monitored due to potential side effects and the risk of developing antibiotic resistance. Quinolones,
are proven very effective in treating a wide range of bacterial infections. They are particularly valued for their
broad-spectrum activity and effectiveness against both Gram-negative and Gram-positive bacteria8.

Volume 30, Issue 8, 2024 553 http://www.gjstx-e.cn/

High Technology Letters ISSN NO : 1006-6748

1.2 Classification of Quinolones

Table no.1 different generations of Quinolones based on its activity spectrum and pharmacological
properties

Types Drugs Structure Targeted Uses References

Microorganisms
Gram Negative Urinary tract 15
except infections
(Nalidixic acid)
1st Generation

Pseudomonas

Gram-negative Pyelonephritis, 15 &16

organisms, sexually
Pseudomonas transmitted
species, few Gram- diseases, urinary
positive organisms tract infections
including
2nd Generation
( Ciprofloxacin)

Staphylococcus
aureus except
Streptococcus
pneumoniae

Gram-negative Chronic 16 & 17

organisms, Gram- Bronchitis,
positive, penicillin- chronic
sensitive and obstructive
3rd Generation
(Levofloxacin,)

penicillin-resistant pulmonary
Streptococcus disorder,
pneumoniae acquired
pneumonia

Volume 30, Issue 8, 2024 554 http://www.gjstx-e.cn/

High Technology Letters ISSN NO : 1006-6748

Gram-negative Intra-abdominal 17
organisms and infections,
Gram-positive, nosocomial
penicillin- sensitive pneumonia,
and penicillin- pelvic infections,
resistant chronic bacterial
4th Generation
(Trovafloxacin)

Streptococcus infections
pneumoniae and
expanded activity
against atypical
pathogens and broad
anaerobic coverage

1.3 In-vitro Activities of Quinolones against Plasmodium Species at Liver and Blood Stages

Among the various fluoroquinolone antibiotic, ciprofloxacin is very commonly used to treat many bacterial
infections. This covers infections of the skin, respiratory tract, kidneys, bones and joints, intra-abdominal
infections, typhoid fever, and some forms of infectious diarrhoea also. It is used in conjunction to other antibiotics
for certain infections. It can be administered intravenously, orally, as eye, ear, or ocular drops.9
Recently, an in-vitro study was conducted to examine the efficacy of various quinolones against the erythrocytic
stages of P. falciparum, as well as the liver stages of both P. falciparum and P. yoelii. P. falciparum cultivated in
red blood cells that was both susceptible to and resistant to chloroquine was inhibited by all of the chemicals.
According to the logarithm of the drug concentration and extended incubation, there inhibitory action was
intensified gradually. Among 25 different types of quinolones, the best results were seen with ciprofloxacin,
trovafloxacin, and grepafloxacin, which showed almost 50% inhibitory concentrations by the use of less than 10
μg/ml against both the strains. The only drugs that shown an inhibitory impact against the hepatic stages of P.
falciparum and P. yoelii were grepafloxacin, piromidic acid, and trovafloxacin. These drugs also caused a
reduction in both the quantity and size of schizonts in treated cultures. Consequently, quinolones may be able to
treat or prevent malaria by unique antiparasitic effect against erythrocytic and hepatic stages of Plasmodium.10
Nowadays, need for new antimalarial drug development is critical, as many evidences of multidrug-resistant were
seen particularly in P. falciparum treatment. Since, quinolones medications have demonstrated in-vitro
antimalarial action against both chloroquine-sensitive and chloroquine-resistant P. falciparum. Therefore,
quinolones and its derivatives (fluoroquinolones) could be suggested as treatments for malaria. However, all of
these investigations, meanwhile, were limited to the erythrocytic stages of P. falciparum, and there is currently no
evidence available regarding the possible effects of the medications against the parasite's hepatic development11.
Furthermore, an earlier study was designed to evaluate the effect of inoculum size of P. falciparum with
chloroquine dose by Gluzman et al. In which, it was reported that upon multiplying the number of parasitized
erythrocytes in their test system by a hundred-fold, the amounts of chloroquine needed to cause a 50% inhibitory
effect increased by a factor of five to seven. The depletion of chloroquine from the extracellular media by
parasitized erythrocytes was linked to this activity. In addition, ciprofloxacin IC50 against P. falciparum at levels
of parasitaemia ranging from 0.25 to 4.0% were also measured. The ciprofloxacin IC50 values against.
Moreover, activity of ciprofloxacin against Vietnam strain (anti-VNS) P. falciparum was also reported when it
was evaluated in combination with either Novobiocin or Tetracycline. Tetracyclines are ribosomal protein
synthesis inhibitors that work well against the P. falciparum's erythrocytic asexual phases in this system. The anti-
VNS efficacy of ciprofloxacin and tetracycline was evaluated in combination, the ratio of IC50 of an antibiotic in
combination to the IC50 of alone treatment was used to calculate the fractional inhibitory concentration (FIC) of
each antibiotic, where the FIC in combination indicated modest additive effects12.

Volume 30, Issue 8, 2024 555 http://www.gjstx-e.cn/

High Technology Letters ISSN NO : 1006-6748

1.4 A strategy to potentiate the Antimalarial Activity of Quinolone

The derivatization of the fluoroquinolone ciprofloxacin greatly increases its antimalarial activity by combining
bio-organometallic chemistry and the prodrug approach.

Compound A Compound B

Figure 1: Compound A and Compound B

These two new achiral compounds A and B as depicted Figure no.1 were found to be 10- to 100-fold more active
than ciprofloxacin against P. falciparum chloroquine-susceptible and chloroquine-resistant strains. These achiral
derivatives killed parasites more rapidly than occurred by ciprofloxacin molecule. Compounds A and B were
revealed to be promising leads, creating a new family of antimalarial agents.13

1.5 Docking studies of Ciprofloxacin [Compound-A]:

Figure 2: Protein molecule Figure 3: Ligand (Ciprofloxacin)

Volume 30, Issue 8, 2024 556 http://www.gjstx-e.cn/

High Technology Letters ISSN NO : 1006-6748

Figure 4. Showing output

Figure 5: Ligand protein interactions

Volume 30, Issue 8, 2024 557 http://www.gjstx-e.cn/

High Technology Letters ISSN NO : 1006-6748

1.6 Docking studies of prodrug of Ciprofloxacin [Compound-B]:

Figure 6. Protein Figure 7. Ligand

Figure 8. Showing Output

Volume 30, Issue 8, 2024 558 http://www.gjstx-e.cn/

High Technology Letters ISSN NO : 1006-6748

Figure 9. Ligand-protein interactions

The relationship between antimalarial activity and docking output involves understanding how computational
docking results correlate with experimental efficacy of antimalarial drugs. Here’s a breakdown of how docking
output can relate to antimalarial activity14

Docking Scores for Antimalarial Activity

Docking scores represent the predicted binding affinity of a ligand (e.g., a drug) to a target protein. A lower
docking score typically indicates a stronger predicted interaction.

Drugs with lower docking scores are often predicted to bind more strongly to the target protein, which could
correlate with higher antimalarial activity. So, Compound B will show greater antimalarial activity than
compound A.15

Docking Scores for Binding Affinity

Binding affinity is the strength of the interaction between the drug and its target protein. This is often expressed
in terms of Gibbs free energy (ΔG\Delta GΔG), with more negative values indicating stronger binding.16

Docking output

The docking output often provides a measure of binding affinity, which helps predict how well the drug might
inhibit the target protein. Effective antimalarial agents should ideally show high binding affinity to key targets in
the malaria parasite.

1.7 Validation and Experimental Correlation of Docking Study

Validation involves confirming that the docking predictions align with actual biological activity. While docking
provides useful predictions, experimental validation is crucial. In vitro and in vivo tests are required to confirm
that the predicted binding translates to actual antimalarial efficacy. Docking results are often used to prioritize
compounds for further testing. In summary, while docking output provides valuable insights into the potential
binding affinity and interaction of antimalarial drugs with their targets, the ultimate measure of antimalarial
activity comes from experimental testing. Docking helps guide the selection of promising candidates for further
development and testing17.

II.CONCLUSION
One potential method to increase the anti-malarial effectiveness of quinolones is to modify their structural
makeup. Our research shows that certain modifications to the functional groups and core structure of quinolones
can greatly boost their anti-Plasmodium falciparum activity. Interestingly, molecules with specific changes
showed enhanced selectivity and potency, resolving some of the issues with conventional quinolones. The
aforementioned findings highlight the possibility of enhancing quinolone derivatives to surmount resistance and

Volume 30, Issue 8, 2024 559 http://www.gjstx-e.cn/

High Technology Letters ISSN NO : 1006-6748

enhance therapeutic effectiveness when treating malaria. In order to confirm these modified quinolones' safety
and efficacy and to further investigate their potential as effective anti-malarial drugs, future studies should
concentrate on their in vivo evaluation
.
IV. CONFLICT OF INTEREST
Authors declare that there is no conflict of interest

REFERENCES
1. Moussaoui O, Byadi S, Hachim ME, Sghyar R, Bahsis L, Moslova K, Aboulmouhajir A, Rodi YK, Podlipnik
Č, El Mestafa EL, Chakroune S, “Selective synthesis of novel quinolones-amino esters as potential
antibacterial and antifungal agents: Experimental, mechanistic study, docking and molecular dynamic
simulations”, Journal of Molecular Structure. pp: 1241-1306, (2021)
2. Patel AJ, Patel MP, Dholakia AB, Patel VC, Patel DS, “Antitubercular, antimalarial activity and molecular
docking study of new synthesized 7-chloroquinoline derivatives”, Polycyclic Aromatic Compounds. pp-
4717-25. (2022)
3. Patel OP, Beteck RM, Legoabe LJ, “Antimalarial application of quinones: A recent update”. European Journal
of Medicinal Chemistry, pp-210-215. (2021)
4. Mulula A, Bouzina AD, Nsomue J, Mambu HB, Tshingamb MN, Zaki A. Synthesis, “In-vitro Antimalarial
Activity and In silico Molecular Docking Study of Amino Chalcone Derivatives from 1-(2-aminophenyl)-3-
(4-substituted-phenyl) prop-2-en-1-one and Dihydroquinolone Derivatives”. Journal of Advanced Pharmacy
Research, Pp-133-43. (2023)
5. Hadni H, Elhallaoui M, “3D-QSAR, docking and ADMET properties of aurone analogues as antimalarial
agents”, (2023)
6. Hadni H, Elhallaoui M, “2D and 3D-QSAR, molecular docking and ADMET properties in silico studies of
azaaurones as antimalarial agents”, New Journal of Chemistry, pp-6553-65.(2022)
7. Qidwai T, “QSAR modeling, docking and ADMET studies for exploration of potential anti-malarial
compounds against Plasmodium falciparum”, In Silico Pharmacology. pp-1-3. (2017)
8. Adeniji SE, Shallangwa GA, Arthur DE, Abdullahi M, Mahmoud AY, Haruna A, “Quantum modelling and
molecular docking evaluation of some selected quinoline derivatives as anti-tubercular agents”. (2020)
9. Beheshti A, Pourbasheer E, Nekoei M, Vahdani S, “QSAR modeling of antimalarial activity of urea
derivatives using genetic algorithm–multiple linear regressions”,Journal of Saudi Chemical Society. pp282-
90. (2016)
10. Khaldan A, Bouamrane S, El-mernissi R, Alaqarbeh M, Hajji H, Alsakhen N, Maghat H, Ajana MA, Sbai A,
Bouachrine M, Lakhlifi T, “Computational study of quinoline-based thiadiazole compounds as potential
antileishmanial inhibitors”, New Journal of Chemistry. pp-17554-76. (2022)
11. Hadni H, Elhallaoui M, “3D-QSAR, docking and ADMET properties of aurone analogues as antimalarial
agents”, Heliyon. (2020)
12. Ojha PK, Roy K, “Chemometric modeling, docking and in silico design of triazolopyrimidine-based
dihydroorotate dehydrogenase inhibitors as antimalarials”, European journal of medicinal chemistry. pp-
4645-56. (2010)
13. Cheng F, Shen J, Luo X, Zhu W, Gu J, Ji R, Jiang H, Chen K, “Molecular docking and 3-D-QSAR studies on
the possible antimalarial mechanism of artemisinin analogues”, Bioorganic & medicinal chemistry. pp-2883-
91.(2002)
14. Beheshti A, Pourbasheer E, Nekoei M, Vahdani S, “QSAR modeling of antimalarial activity of urea
derivatives using genetic algorithm–multiple linear regressions”, Journal of Saudi Chemical Society. pp-282-
90. (2016)
15. Chaniad P, Mungthin M, Payaka A, Viriyavejakul P, Punsawad C, “Antimalarial properties and molecular
docking analysis of compounds from Dioscorea bulbifera L. as new antimalarial agent candidates”, BMC
complementary medicine and therapies. (2021)
16. Suresh PS, Kesarwani V, Kumari S, Shankar R, Sharma U, Bisbenzylisoquinolines from Cissampelos pareira
L. as antimalarial agents: Molecular docking, pharmacokinetics analysis, and molecular dynamic simulation
studies, Computational Biology and Chemistry. (2023)

Volume 30, Issue 8, 2024 560 http://www.gjstx-e.cn/

High Technology Letters ISSN NO : 1006-6748

17. Kumar A, Jain S, Chauhan S, Aggarwal S, Saini D, “Novel hybrids of quinoline with pyrazolylchalcones as
potential antimalarial agents: synthesis, biological evaluation, molecular docking and ADME
prediction”,Chemico-Biological Interactions. (2023)

Volume 30, Issue 8, 2024 561 http://www.gjstx-e.cn/