In Silico Molecular Modeling Studies on Novel Imidazole Derivatives and Their Potential Anti-Tubercular Activities Utilizing Advanced CADD Tools

Mycobacterium tuberculosis causes tuberculosis, a communicable bacterial infection that primarily affects the lungs before spreading to other organs. This disease has not been completely overcome yet, and one-third of the world's population still suffers from it. The scenario regarding TB has worsened since the COVID-19 pandemic, as many patients health has been compromised during and after their COVID infection. The Mycobacterium tuberculosis can attack these patients, whose immune systems have become very weak, putting them at a higher risk of infection. Additionally, some drugs are becoming ineffective against TB because COVID-19 treatment often involves various medications, including some TB drugs. As a result, first line and second line antibiotics for TB may no longer be effective due to the body developing resistance. It's also reported that patients who were diagnosed with TB early but took a long time to recover might face complications. While the initial infection can be cured, subsequent infections may not respond to the same medications, as the bacteria may resist treatment through chemotherapeutic classification. This highlights why tuberculosis remains a critical public health issue today, which is why I have chosen to focus on TB. There is nothing new about TB; it is caused by Mycobacterium tuberculosis, with symptoms including coughing up blood, sneezing, fatigue, fever, weight loss, chest pain, and loss of appetite. It is usually identified by several sputum tests and chest X-rays.  Different countries like India (28%), Indonesia (9.2%), China (7.4%), and Philippines (7.0%) are having highest data in associated with TB. While only a small percentage of those with latent tuberculosis infection (LTBI) progress to active TB, approximately 10 million individuals have fallen ill with this disease each year since 2000. The mortality rate is equally alarming, with an estimated 1.4 to over 2 million lives lost annually from 2000 to 2021. According to previous report, TB symptoms present exceed than a million in the year of 2021. 1.4 million individuals from HIV-negative and 0.2 million individuals from HIV-positive were also affected by TB. Importantly, before the COVID-19 pandemic, TB fatalities consistently surpassed those caused by any other single infectious agent, including HIV/AIDS. This stark reality highlights the urgent and immediate need for sustained action against this preventable and treatable disease. [1, 2]

Existing Treatment of Tuberculosis:

The standard treatment for drug-sensitive tuberculosis (TB) is a six-month regimen of four key medications: isoniazid, rifampicin, ethambutol, and pyrazinamide. For drug resistant TB, treatment is individualized based on resistance profiles and typically involves longer durations and additional medications, demonstrating a strong commitment to patient care.[1,2]

First Line Anti TB Drugs: [3-4]

Some existing drugs with more efficacy and lower side effects are useful to treat multidrug sensitive TB.

Second Line Anti TB Drugs: [5-7]

These are used when TB is resistant to first-line drugs, especially in MDR-TB (Multidrug Resistant TB) and XDR-TB (Extensively Drug Resistant TB) cases. They are often less effective, more toxic, and more expensive.

Table 2: Second Line Anti TB Drugs - Fluoroquinolones (core second-line agents)

Table 3: Second Line Anti TB Drugs - Injectable Agents (used less often now)

Table 4: Second Line Anti TB Drugs - Newer Drugs

Multidrug Resistance of Anti TB Drugs:

Multidrug resistant TB is very critical form of TB in where maximum existing drugs are tolerated and resistant to TB causative organism like Mycobacterium tuberculosis strains.

1. Isoniazid (INH)
2. Rifampin (RIF)

These are the two most powerful first-line anti-TB drugs, so resistance makes the infection much harder to treat. [4-8]

Causes of MDR-TB [8-9]:

Table 5: Causes of MDR-TB

Pathophysiology of Tuberculosis:

Tuberculosis (TB) Stages:                                           

1. Primary Infection

2. Latent Infection

3. Active Infection

Mycobacterium tuberculosis causes initial infections, with around 95% being asymptomatic. Only 5-10% progress to active disease.

Primary TB infection: It occurs through inhaling small particles that reach the lungs. A single droplet can initiate infection. Once inside alveolar macrophages, bacilli may replicate, leading to macrophage death and inflammation. TB germ enters into local lymph nodes and accumulates in the whole body. At this stage, TB is not communicable.

Latent TB Infection: Most primary infections become latent, with the immune system suppressing bacillary growth within three weeks. TB germ converted into granulomas for many years. Latent sites are active, not entirely dormant. IGRA and tuberculin skin tests are having the results of positive during this part of disease. Sometimes, primary infections can cause severe illness, particularly in young or immunosuppressed individuals. Extrapulmonary TB can occur without lung involvement, with lymphadenopathy being the most common form. At this stage, TB is not communicable.

Active TB Disease: Healthy individuals have a 5-10% lifetime risk of developing active TB, especially within the first two years. Reactivation commonly occurs in the lungs but can also affect other organs. Impaired immunity significantly increases reactivation risk. For instance, HIV co-infected patients not on therapy have a 10% annual risk of active TB. Other risk factors include diabetes, head and neck cancer, and chronic kidney disease. Awareness of these stages and risk factors is essential for effective TB diagnosis, treatment, and prevention. [10-11]

MATERIAL AND METHODOLOGY

a) Software and Web servers: [12-25]

Pub Chem

Protein Data Bank (PDB)

CB-DOCK2

Auto Dock Tools

Swiss ADME

Pharmit

b) Methods:

Figure 1: Methodology

Lipinski's rule: [26]

1) The total number of hydrogen bond donors must be within five.

2) The total number of hydrogen bond acceptors must be within ten.

3)There should be no more than 500 Daltons of molecular mass.

4) Log P needs to be fewer than five.

RESULTS

Table 6: List of Standard Compound

Table 7: List of Test Samples

SL.No.	Test Samples	Structure
1	Test Sample 1
2	Test Sample 2
3	Test Sample 3
4	Test Sample 4
5	Test Sample 5
6	Test Sample 6
7	Test Sample 7
8	Test Sample 8
9	Test Sample 9
10	Test Sample 10

Table 8: Receptor Activate Site (Coordinates

Sl. No.	Name of the Standard Compound	Docking Result [Binding Energy (kcal/mol)]	Molecular Docking
1	Delamanid	-11.8

Table 10: Molecular Docking of Test Samples to the Active Sites of 1KPG