Unveiling dynamics of nitrogen content and selected nitrogen heterocycles in thrombin inhibitors: a ceteris paribus approach

ABSTRACT

Background

Despite the progress in comprehending molecular design principles and biochemical processes associated with thrombin inhibition, there is a crucial need to optimize efforts and curtail the recurrence of synthesis-testing cycles. Nitrogen and N-heterocycles are key features of many anti-thrombin drugs. Hence, a pragmatic analysis of nitrogen and N-heterocycles in thrombin inhibitors is important throughout the drug discovery pipeline. In the present work, the authors present an analysis with a specific focus on understanding the occurrence and distribution of nitrogen and selected N-heterocycles in the realm of thrombin inhibitors.

Research design and methods

A dataset comprising 4359 thrombin inhibitors is used to scrutinize various categories of nitrogen atoms such as ring, non-ring, aromatic, and non-aromatic. In addition, selected aromatic and aliphatic N-heterocycles have been analyzed.

Results

The analysis indicates that ~62% of thrombin inhibitors possess five or fewer nitrogen atoms. Substituted N-heterocycles have a high occurrence, like pyrrolidine (23.24%), pyridine (20.56%), piperidine (16.10%), thiazole (9.61%), imidazole (7.36%), etc. in thrombin inhibitors.

Conclusions

The majority of active thrombin inhibitors contain nitrogen atoms close to 5 and a combination of N-heterocycles like pyrrolidine, pyridine, piperidine, etc. This analysis provides crucial insights to optimize the transformation of lead compounds into potential anti-thrombin inhibitors.

GRAPHICAL ABSTRACT

KEYWORDS:

• Drug discovery
• nitrogen rings
• pyrrolidine
• pyridine
• piperidine
• thrombin inhibitors

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Data availability statement

The data, the details of the molecules and the occurrence of selected heterocyclic rings in the present dataset are available as supplementary material.

Author contributions

VH Masand, S Al-Hussain and MEA Zaki were responsible for the article’s conception and design; VH Masand, AA Al-Mutairi, A Samad and AS Alqahtani were responsible for the collection, analysis and interpretation of the data; VH Masand, AM Alafeefy and AY Alzahrani created images, writing and responsible for drafting the paper. VH Masand, RD Jawarkar, S Al-Hussain and MEA Zaki were responsible for revising the article critically for intellectual content. Finally, VH Masand, RD Jawarkar, AA Al-Mutairi, A Samad, AS Alqahtani AM Alafeefy and AY Alzahrani were responsible for further revision of the manuscript. All authors reviewed and approved the manuscript.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17460441.2024.2368743.

Additional information

Funding

This work was supported by the Deanship of Scientific Research at Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia.