Pyrimidine Derivatives: A Comprehensive Review of Synthetic Strategies, Biological Activities and In-Silico Studies

1.1 Significance of the pyrimidine scaffold

Heterocycles containing nitrogen are among the scaffolds most often used in drug discovery, and pyrimidine is a prominent member of the group. Cytosine, thymine and uracil in DNA and RNA are pyrimidines, and the ring also appears in thiamine and in many natural products^1,2. Because biological systems already contain proteins that recognize this motif, pyrimidine-containing molecules readily bind enzymes, receptors and nucleic acids, which is one explanation for the diversity of pharmacological effects described for them^3,4. Review articles repeatedly mention anticancer, antibacterial, antifungal, antiviral, anti-inflammatory, antitubercular and antimalarial actions for these compounds^5–8. Ring-fused pyrimidines deserve particular attention, since adding a second ring has been reported to modify potency. The resulting thiazolo-, pyrido-, pyrazolo- and thieno-pyrimidines frequently serve as bio-isosteres of purines^6,9.

1.2 Structure and numbering

Positions in the pyrimidine ring (C₄H₄N₂) are labelled N1, C2, N3, C4, C5 and C6 (Figure 1). Because the two nitrogen’s draw electron density out of the ring, the system is π-deficient and C2, C4 and C6 are electron-poor. Nucleophilic substitution, for example the exchange of a chlorine atom for an amine, therefore occurs preferentially at these carbons. C5 retains more electron density than the other carbons, so electrophilic reactions such as halogenation and nitration take place there. Although C4 and C6 are interchangeable in the unsubstituted ring, they stop being equivalent when substituents are present or when another ring is fused on. This dependence of reactivity on position affects both the synthetic chemistry (Section 2) and the SAR (Section 4).

Figure 1: Structure and numbering of the pyrimidine ring.

1.3 Scope of this review

The article is organized as follows. Section 2 deals with synthesis, Section 3 with biological activities, Section 4 with SAR and Section 5 with in-silico work. Section 6 summarizes advances made between 2020 and 2026, Section 7 offers a critical analysis, Section 8 lists research gaps, Section 9 outlines future directions and Section 10 concludes.

2. SYNTHETIC STRATEGIES

Pyrimidine syntheses can be placed in four groups: classical condensation reactions that form the ring, multicomponent and green procedures, functionalization of an existing ring with transition-metal catalysts, and annulation strategies that deliver fused systems^5,6 (Figure 2, Table 1).

Figure 2: Main synthetic routes to pyrimidine and fused-pyrimidine libraries.

2.1 Classical ring construction

Traditional approaches generally combine a three-carbon component with an N–C–N component such as urea, thiourea, guanidine or an amidine. Biginelli's reaction is the standard example: an aldehyde, a β-ketoester and urea or thiourea are heated together with an acid catalyst in a single pot, yielding 3,4-dihydropyrimidin-2 (1H)-ones or their thio analogues. Its scope and subsequent modifications have been reviewed at length^10,11. Pinner-type condensation of a 1,3-dicarbonyl compound with an amidine gives pyrimidines substituted at C2, while 4,6-diarylpyrimidines result when chalcones are cyclised with guanidine, urea or thiourea^5,8.

2.2 Multicomponent and green methods

In multicomponent reactions (MCRs), several reactants are assembled into the ring in one step with little waste. As an illustration, ethanol-based condensation of an aldehyde, a nitrile bearing an active methylene group and urea or thiourea has led to pyrimidine-5-carbonitriles, cyanothiouracils and pyrano-pyrimidines^7,8. Current methods increasingly replace severe conditions with microwave or ultrasound heating, reusable catalysts and reactions without solvent⁵.

2.3 Transition-metal-catalysed functionalization

Palladium, nickel and copper catalysts can modify a pyrimidine ring that has already been formed, without rebuilding it. One recent review compares such direct functionalization approaches and notes advantages in the number of steps, regiocontrol and ease of scale-up¹². They are especially useful for adding diversity at a late stage, which helps when SAR libraries are being prepared.

2.4 Fused-pyrimidine systems

Two general tactics lead to fused pyrimidines. One builds a further ring on a pyrimidine whose neighbouring substituents are suitably reactive, as is the case for 6-aminouracils and thioxopyrimidines. The other forms the pyrimidine ring on a pre-existing heterocycle that carries an amino-carbonyl or amino-nitrile pair. Fused systems may be sorted according to the size of the new ring, anywhere from five to eight atoms⁶. Pyrazolo[3,4-d]- and pyrazolo[1,5-a]pyrimidines are of special importance as scaffolds for kinase inhibitors^13–15.

Table 1: Overview of Synthetic Strategies for Pyrimidine Scaffolds.

3. BIOLOGICAL ACTIVITIES

Figure 3 gives an overview of the activity classes, and Table 2 collects representative marketed or clinical-stage drugs built on pyrimidine^3,5.

Figure 3: Major biological activities of pyrimidine derivatives, with example mechanisms or targets.

3.1 Antibacterial activity

Antimicrobial resistance is a growing worldwide threat. A survey covering over 200 pyrimidines listed compounds with one to four substituents that display antimicrobial action; trimethoprim-type 2,4-diaminopyrimidine antifolates are among them¹⁶. Pyrimidines had already been described as bactericidal, fungicidal and virucidal agents in an earlier overview⁴. A review published in 2026 addresses pyrimidine nucleosides, sorting them into cytosine analogues and uracil/thymine analogues. To adjust target binding, passage through membranes and metabolic stability, chemists introduce modifications such as lipidation and selenylation. Because these molecules are prodrugs, intracellular phosphorylation is needed before they can interfere with nucleic acid synthesis. According to that review, translation to the clinic is held back by toxicity to the host, a narrow spectrum and scarce information on resistance¹⁷.

3.2 Anticancer activity

Pyrimidine analogues were among the first rationally designed antimetabolites. The main actions of 5-fluorouracil are inhibition of thymidylate synthase and incorporation into RNA and DNA¹⁸; gemcitabine and cytarabine are further nucleoside antimetabolites of this type¹². At present, however, most effort is directed at kinase inhibition. Approved kinase inhibitors with a pyrimidine or fused-pyrimidine core include imatinib, a phenylaminopyrimidine acting on BCR-ABL¹⁹; osimertinib, which inhibits EGFR including the T790M mutant²⁰; and palbociclib, a pyrido[2,3-d]pyrimidine that blocks CDK4/6²¹. Roskoski has reviewed the properties of FDA-approved drugs in this class²².

Because the pyrazolo[3,4-d]pyrimidine bicycle looks like the adenine ring of ATP, it can reproduce the contacts that ATP makes with the hinge region of kinases. Ibrutinib, a BTK inhibitor, is based on this core, and parsaclisib, sapanisertib and umbralisib are reported to have reached clinical trials¹³. Its isomer, pyrazolo[1,5-a]pyrimidine, has been tested against a wide range of targets such as CK2, EGFR, B-Raf, MEK, PDE4, BCL6, DRAK1, CDK1/2 and Pim-1¹⁴. More recent series cover thiazolo[4,5-d]pyrimidines (CDK, VEGFR, PI3K)⁹, pyrido[2,3-d]pyrimidines (EGFR)²³, thieno-triazolopyrimidines (EGFR, PI3K)²⁴ and pyrimidine carboxylates (VEGFR)²⁵. Among thiazolyl-pyrimidines designed against CK2α, five compounds had IC₅₀ values between roughly 2.4 and 5.0 µM, whereas doxorubicin gave 6.18 µM in the same assay²⁶.

3.3 Antiviral activity

Nucleoside analogues based on pyrimidines are central to antiviral treatment. Zidovudine, an analogue of thymidine, was the first agent shown to block HIV replication in vitro²⁷; overviews of nucleoside and non-nucleoside reverse-transcriptase inhibitors are available²⁸. Rilpivirine, a diarylpyrimidine, illustrates that a pyrimidine scaffold without a sugar can also produce strong anti-HIV drugs²⁹. Anti-HIV and other antiviral effects have also often been described for fused pyrimidines⁶.

3.4 Antitubercular activity

Clinical progression of GSK 2556286, TBA-7371 and SPR720 stimulated interest in pyrimidines for tuberculosis. A recent review sorts pyrimidine-containing compounds by their targets and discusses SAR for each group³⁰. In a distinct body of work, pyrimidine nucleosides and nucleotides were examined as inhibitors of thymidine monophosphate kinase from Mycobacterium tuberculosis (TMPKmt), with SAR and computational analysis in support³¹.

3.5 Antifungal activity

Flucytosine (5-fluorocytosine) is the best-known pyrimidine antifungal. Fungal cells that are susceptible transform it into 5-fluorouracil, and one review is devoted to its pharmacology, clinical use and toxicity³². Wider reviews of the scaffold discuss other antifungal pyrimidines, among them fused ones^5,8.

3.6 Anti-inflammatory and other activities

Several mediators of inflammation, including prostaglandin E2, inducible nitric oxide synthase, TNF-α, NF-κB, leukotrienes and some interleukins, are thought to be suppressed by anti-inflammatory pyrimidines, either at the level of expression or of activity. The SAR of these compounds was analysed systematically in a 2021 review³³. COX-1 and COX-2 are inhibited by some pyrimidines, and pyrimidine acrylamides have been put forward as starting points for antioxidants¹². Antimalarial, anticonvulsant, antihypertensive and other effects have been reported too^6,7.

Table 2: Representative Marketed Pyrimidine-Based Drugs and Activities.

4. STRUCTURE–ACTIVITY RELATIONSHIP (SAR)

How SAR in pyrimidines plays out depends on the target and the chemical series, but the literature reveals several repeating trends (Figure 4, Table 3). Fusing a ring is the most widely applicable design tool; a review of ring-fused pyrimidines points out that fused systems frequently show additive effects on biological efficacy compared with the parent ring⁶.

Figure 4: SAR map of the pyrimidine ring showing common substituent effects reported in the literature.

In kinase inhibitors the ring nitrogens, together with an amino group, usually hydrogen-bond to the hinge region; imatinib and osimertinib, both 2-anilinopyrimidines, are examples of this binding mode^19,20. For pyrazolo[3,4-d]pyrimidines, changing groups at N1, C3, C4 and C6 shifts kinase selectivity. A thiophenethyl group at C6 was required for anticancer potency in one CDK2 series, while the substitution on the C4-aryl group determined CDK2 inhibition¹³. At C5, fluorine characterises the antimetabolites 5-fluorouracil and flucytosine^18,32, and a carbonitrile group defines another family of anticancer, antimicrobial and antitubercular compounds⁷. Detailed SAR work on anti-inflammatory pyrimidines has pinpointed substitution patterns that strengthen COX or mediator inhibition without raising toxicity³³.

Table 3: Position-By-Position SAR Trends in Pyrimidine Derivatives.

5. IN-SILICO STUDIES

Computational methods now routinely accompany synthesis and biological testing: they help refine pharmacophores, rank candidates and explain observed activity³⁴. Figure 5 shows a typical workflow, and Table 4 lists representative studies.

Figure 5: Typical integrated in-silico workflow for designing pyrimidine leads.

5.1 Molecular docking

Docking predicts how a ligand sits in a protein binding site and how strongly it binds, making it the main technique of structure-based design³⁵. Programs in common use are AutoDock Vina³⁶, the Molecular Operating Environment (MOE) and Schrödinger Maestro. Published pyrimidine studies include thiazolopyrimidines docked to CDK1, VEGFR-2 and PI3Kα⁹, pyrido[2,3-d]pyrimidines to EGFR²³, pyrimidine carboxylates to VEGFR using MOE²⁵, and thiazolyl-pyrimidines to CK2α, where docking agreed with in-vitro cytotoxicity²⁶.

5.2 Molecular dynamics

Since docking usually holds the protein almost rigid, MD simulations with explicit solvent are used to see whether a docked complex remains stable³⁷, and GROMACS is a popular engine for this³⁸. The usual results are RMSD, RMSF, hydrogen-bond occupancy and binding free energies by MM/GBSA or MM/PBSA. Examples include a 100-ns run with MM/PBSA on pyrimidine FAK inhibitors suggested by 3D-QSAR³⁹, a 100-ns run with MM/GBSA backing a pyrimidine-2,4-dione thymidylate synthase inhibitor⁴⁰, and 200-ns runs on thieno[2,3-d]pyrimidine cholinesterase inhibitors⁴¹.

5.3 ADME/ADMET prediction

Absorption, distribution, metabolism, excretion and toxicity are usually predicted with free tools such as SwissADME⁴² and pkCSM⁴³. ADMET analysis of pyrido[2,3-d]pyrimidine EGFR candidates showed they obeyed Lipinski's rule, had no PAINS or Brenk alerts (unlike erlotinib) and were predicted to be well absorbed from the gut²³. Good oral bioavailability was likewise predicted for thiazolyl-pyrimidines²⁶.

5.4 Drug-likeness

Lipinski's rule of five⁴⁴ and the Veber criteria, which concern polar surface area and the number of rotatable bonds⁴⁵, are used to judge drug-likeness; PAINS filters add to these by removing chemotypes that tend to interfere with assays⁴⁶. Earlier in the process, QSAR and pharmacophore models⁴⁷ propose new structures. A Maestro-based study found that 43 pyrimidine derivatives cleared ADMET screening, three of which were predicted to bind DNA most tightly³⁴.

Table 4: Representative In-Silico Studies of Pyrimidine Derivatives.

6. RECENT ADVANCES (2020–2026)

Kinase-focused scaffolds. A review from 2020 follows the maturation of pyrazolo[3,4-d]pyrimidines, covering ibrutinib-derived covalent BTK inhibitors and BTK-targeting PROTACs intended to circumvent mutation of the reactive cysteine¹³. A 2025 review treated pyrazolo[1,5-a]pyrimidines as protein kinase inhibitors across at least nine kinase families¹⁴.

Anti-infectives. Clinical trials have been reached by pyrimidine-based antitubercular compounds³⁰, and in view of antimicrobial resistance pyrimidine nucleosides are again being considered as antibacterial leads¹⁷.

Inflammation and synthesis. The SAR of anti-inflammatory pyrimidines was brought together in 2021³³, and a 2025 review covered direct functionalization chemistry¹².

New anticancer series. Pyrido[2,3-d]pyrimidine EGFR inhibitors (2026)²³ and thiazolyl-pyrimidines active on CK2α (2025)²⁶ typify what is now a standard pipeline: synthesis, assay, docking and ADMET prediction.

Wider indications and longer simulations. Dual cholinesterase inhibitors for Alzheimer's disease, supported by 200-ns MD⁴¹, and α-glucosidase inhibitors studied by QSAR, docking, ADMET and MD⁴⁹ show that pyrimidine design is moving into new areas; thymidylate synthase inhibitors are being developed using 100-ns MD as well⁴⁰.

7. CRITICAL ANALYSIS

Potency versus cellular activity. IC₅₀ values from enzyme assays predict cellular efficacy poorly. In a set of BTK inhibitors derived from ibrutinib, a vinyl sulfonamide with a lower enzyme IC₅₀ than ibrutinib had no useful antiproliferative activity in two B-cell leukaemia lines, but an acetamide analogue that was weaker against the enzyme killed cells at low micromolar concentrations¹³. Relying on a single enzyme assay for optimisation may thus mislead.

Selectivity and safety. Kinases have very similar ATP sites, which makes selectivity a constant problem. Ibrutinib is only moderately selective, and its off-target toxicity has been connected to a conserved cysteine that other kinases also carry; in the MER-inhibitor series, hERG liabilities forced redesign as well¹³.

Comparisons and controls. Whether new compounds beat a reference drug such as doxorubicin²⁶ depends on cell line, exposure time and assay format. IC₅₀ values or docking scores from different papers cannot be compared directly when the software, force fields and protein structures differ.

Predictive tools are hypotheses. Docking, ADMET web servers and rule-based filters^42–44 are cheap but only approximate. Obeying Lipinski's rule or showing no PAINS alerts guarantees neither oral bioavailability nor safety. MD adds rigour, yet simulations of 100–200 ns are brief compared with many binding events, and several reports use only one replica.

Translational gap. A large share of pyrimidine studies end with cytotoxicity in cell lines and computational ranking. Nucleoside antibacterials, by contrast, are openly acknowledged to face unresolved clinical barriers in host toxicity and narrow spectrum¹⁷.

8. RESEARCH GAPS

• Experimental binding evidence (crystallography, SPR, thermal-shift assays) or in-vivo pharmacokinetics is seldom combined with in-silico predictions.
• Little is known about resistance to pyrimidine nucleosides, and mechanistic work seldom looks beyond nucleic acid synthesis¹⁷.
• Controls, cell lines, docking protocols and numbers of MD replicates are described inconsistently, so meta-analysis is not possible.
• The range of targets is limited: most recent studies go back to EGFR, VEGFR, CDK and PI3K, leaving pyrimidine-biosynthesis targets in pathogens and antitubercular targets with little chemical precedent largely unexplored^30,31.
• Although greener routes are often claimed, green-chemistry metrics are seldom given for pyrimidine syntheses⁵.

9. FUTURE PERSPECTIVES

• Targeted protein degradation. BTK-directed PROTACs based on a pyrazolo[3,4-d]pyrimidine core demonstrate that degraders can overcome resistance arising from cysteine mutation¹³.
• Covalent and multi-target design. Covalent warheads and dual- or multi-kinase profiles, steered by kinome-wide selectivity screening^13,14.
• Nucleoside prodrugs. Antibacterial pyrimidine prodrugs designed around activating enzymes, together with combination therapy to extend the spectrum¹⁷.
• Validated computational pipelines. Workflows connecting QSAR, docking, replicated MD with free-energy calculations and ADMET, with experimental confirmation to follow^37,39,49.
• Sustainable synthesis. Catalytic C–H functionalization and multicomponent routes, reported together with green metrics^5,12.

CONCLUSION

Pyrimidine remains among the most fruitful scaffolds in drug discovery, resting on well-established synthetic chemistry, drugs already validated in the clinic and abundant SAR knowledge. Computational tools speed up the identification of leads, but they are only as useful as the experimental validation and consistent reporting behind them. Future progress will probably come from selective and covalent kinase chemistry, nucleoside prodrugs for infections, targeted degradation and computational pipelines that are rigorously validated.

ACKNOWLEDGMENT

[Authors to add acknowledgment, if any.]

CONFLICT OF INTEREST

[Authors to declare any conflicts of interest, or state that there are none.]

REFERENCES

1. Lagoja IM. Pyrimidine as constituent of natural biologically active compounds. Chem Biodivers. 2005;2 (1):1–50.
2. Jain KS, Chitre TS, Miniyar PB, Kathiravan MK, Bendre VS, Veer VS, et al. Biological and medicinal significance of pyrimidines. Curr Sci. 2006;90 (6):793–803.
3. Kumar S, Narasimhan B. Therapeutic potential of heterocyclic pyrimidine scaffolds. Chem Cent J. 2018;12:38.
4. Kidwai M, Saxena S, Rastogi S, Venkataramanan R. Pyrimidines as anti-infective agents. Curr Med Chem Anti-Infect Agents. 2003;2 (4):269–86. doi:10.2174/1568012033483015
5. Islam MW, Islam MM, Akter R, Limon TR, Vasquez ES, Shaikh MAA, et al. A review on pyrimidine-based derivatives: synthesis and their biological application. J Heterocycl Chem. 2024;61 (7):1159–79. doi:10.1002/jhet.4837
6. Joshi G, Nayyar H, Alex JM, Vishwakarma GS, Mittal S, Kumar R. Pyrimidine-fused derivatives: synthetic strategies and medicinal attributes. Curr Top Med Chem. 2016;16 (28):3175–3210. doi:10.2174/1568026616666160506145046.
7. Edris NA, Kadry HH, Taher AT, Adly ME. Pyrimidine-5-carbonitriles: a review of available synthetic approaches and biological evaluation for promising compounds over the last decade. Egypt J Chem. 2024;67 (9):439–462. doi:10.21608/ejchem.2024.264757.9231.
8. Elkanzi NAA. Synthesis and biological activities of some pyrimidine derivatives: a review. Orient J Chem. 2020;36 (6):1001–1015. doi:10.13005/ojc/360602.
9. El-Khouly OA, Othman DIA, Mostafa AS, Massoud MAM. Thiazolopyrimidine as a promising anticancer pharmacophore: in silico drug design, molecular docking and ADMET prediction studies. Med Sci Forum. 2022;14 (1):4. doi:10.3390/ecmc2022-13313
10. Kappe CO. 100 years of the Biginelli dihydropyrimidine synthesis. Tetrahedron. 1993;49 (32):6937–63.
11. Kappe CO. Recent advances in the Biginelli dihydropyrimidine synthesis. New tricks from an old dog. Acc Chem Res. 2000;33 (12):879–88.
12. Mirfarah A, Hatami S, Shiri A. Comprehensive perspectives of metal and metal-free C–H activation approaches in pyrimidines and related heteroarenes: scope, mechanistic insights, and synthetic utility. RSC Adv. 2025;15 (49):42121–42175. doi:10.1039/D5RA07044A.
13. Baillache DJ, Unciti-Broceta A. Recent developments in anticancer kinase inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold. RSC Med Chem. 2020;11 (10):1112–35. doi:10.1039/d0md00227e
14. Iorkula TH, Osayawe OJ-K, Odogwu DA, Ganiyu LO, Faderin E, Awoyemi RF, et al. Advances in pyrazolo[1,5-a]pyrimidines: synthesis and their role as protein kinase inhibitors in cancer treatment. RSC Adv. 2025;15:3756–3828. doi:10.1039/D4RA07556K.
15. Schenone S, Radi M, Musumeci F, Brullo C, Botta M. Biologically driven synthesis of pyrazolo[3,4-d]pyrimidines as protein kinase inhibitors: an old scaffold as a new tool for medicinal chemistry and chemical biology studies. Chem Rev. 2014;114 (14):7189–238.
16. Sharma V, Chitranshi N, Agarwal AK. Significance and biological importance of pyrimidine in the microbial world. Int J Med Chem. 2014;2014:202784. doi:10.1155/2014/202784
17. Xu B, Li P, Liu J, Li M. Pyrimidine nucleoside: inspiration for novel antimicrobial agent. Front Pharmacol. 2026;17:1773361. doi:10.3389/fphar.2026.1773361
18. Longley DB, Harkin DP, Johnston PG. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3 (5):330–8.
19. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344 (14):1031–7.
20. Cross DAE, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4 (9):1046–61.
21. Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004;3 (11):1427–38.
22. Roskoski R Jr. Properties of FDA-approved small molecule protein kinase inhibitors: a 2020 update. Pharmacol Res. 2020;152:104609.
23. Garmabi H, Matin MM, Sabet-Sarvestani H, Eshghi H. Novel pyrido[2,3-d]pyrimidine derivatives as potential EGFR inhibitors: synthesis and in silico studies. Tetrahedron. 2026;197:135318. doi:10.1016/j.tet.2026.135318.
24. Elsenbawy ESM, Alshehri ZS, Babteen NA, Abdel-Rahman AAH, El-Manawaty MA, Nossier ES, et al. Designing potent anti-cancer agents: synthesis and molecular docking studies of thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidine derivatives. Molecules. 2024;29 (5):1067. doi:10.3390/molecules29051067.
25. Hassan OM, Hameed TM, Sahib HB. Synthesis, characterization, molecular docking and pharmacokinetics of new pyrimidine carboxylate derivatives as potent VEGFR inhibitors. Trop J Pharm Res. 2026;25 (6):815–822. doi:10.4314/tjpr.v25i6.7.15
26. Abolibda TZ, El-Sayed AAA, Farag B, Zaki MEA, Alrehaily A, Elbadawy HM, et al. Novel thiazolyl-pyrimidine derivatives as potential anticancer agents: synthesis, biological evaluation, and molecular docking studies. Results Chem. 2025;13:102008.
27. Mitsuya H, Weinhold KJ, Furman PA, St Clair MH, Lehrman SN, Gallo RC, et al. 3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci USA. 1985;82 (20):7096–100.
28. De Clercq E. Antiviral drugs in current clinical use. J Clin Virol. 2004;30 (2):115–33.
29. Janssen PAJ, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, et al. In search of a novel anti-HIV drug: multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (R278474, rilpivirine). J Med Chem. 2005;48 (6):1901–9.
30. Finger V, Kufa M, Soukup O, Castagnolo D, Roh J, Korabecny J. Pyrimidine derivatives with antitubercular activity. Eur J Med Chem. 2023;246:114946. doi:10.1016/j.ejmech.2022.114946
31. Chitre TS, Asgaonkar KD, Patil SM, Kathiravan MK, Padhye SB. Exploring pyrimidine pharmacophore as thymidine monophosphate kinase inhibitors for antitubercular activity: a review. Curr Top Med Chem. 2016;16 (28):3211–23. doi:10.2174/1568026616666160506130914
32. Vermes A, Guchelaar HJ, Dankert J. Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother. 2000;46 (2):171–9.
33. Rashid H ur, Martines MAU, Duarte AP, Jorge J, Rasool S, Muhammad R, et al. Research developments in the syntheses, anti-inflammatory activities and structure–activity relationships of pyrimidines. RSC Adv. 2021;11 (11):6060–98. doi:10.1039/D0RA10657G
34. Patil SM, Randive V, Mahadik I, Bhandari S, Asgonkar K, Nikalje PY. Pharmacophore optimization using pharmacophore mapping, QSAR, docking, and ADMET screening of novel pyrimidine derivatives as anticancer DNA inhibitors. Lett Org Chem. 2024. doi:10.2174/0115701786301475240503071147.
35. Meng XY, Zhang HX, Mezei M, Cui M. Molecular docking: a powerful approach for structure-based drug discovery. Curr Comput Aided Drug Des. 2011;7 (2):146–57.
36. Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010;31 (2):455–61.
37. Hollingsworth SA, Dror RO. Molecular dynamics simulation for all. Neuron. 2018;99 (6):1129–43.
38. Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, Hess B, et al. GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 2015;1–2:19–25.
39. El Bahi S, Boutalaka M, El Alaouy MA, Bouamrane S, Alaqarbeh M, Choukrad M, et al. Computational investigation of novel pyrimidine derivatives as potent FAK inhibitors via 3D-QSAR, molecular docking, molecular dynamics simulation and retrosynthesis. New J Chem. 2023;47:12816. doi:10.1039/D3NJ02471G.
40. Baziar L, Ataollahi E, Rezaei Z, Abdulkadhim Y, Abdolahi MR, Poustforoosh A, et al. Design, synthesis, and biological evaluation of novel 6-(4-aminopiperidin-1-yl)-substituted benzyl-3-methylpyrimidine-2,4 (1H,3H)-dione derivatives as potential anticancer agents targeting thymidylate synthase. Sci Rep. 2025;15:40991. doi:10.1038/s41598-025-24828-5.
41. Alshamari AK, Magdy N, Basiony EA, et al. Synthesis, biological evaluation, molecular docking and molecular dynamics of substituted thieno[2,3-d]pyrimidine derivatives as potential anti-Alzheimer agents. Int J Mol Sci. 2026;27 (14):6119. doi:10.3390/ijms27146119
42. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7:42717.
43. Pires DEV, Blundell TL, Ascher DB. pkCSM: predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J Med Chem. 2015;58 (9):4066–72.
44. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 1997;23 (1–3):3–25.
45. Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem. 2002;45 (12):2615–23.
46. Baell JB, Holloway GA. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J Med Chem. 2010;53 (7):2719–40.
47. Cherkasov A, Muratov EN, Fourches D, Varnek A, Baskin II, Cronin M, et al. QSAR modeling: where have you been? Where are you going to? J Med Chem. 2014;57 (12):4977–5010.
48. Kokbudak Z, Akkoc S, Karatas H, Tuzun B, Aslan G. In silico and in vitro antiproliferative activity assessment of new Schiff bases. ChemistrySelect. 2022. doi:10.1002/slct.202103679
49. Abchir O, Rossafi B, Bouribab A, Es-Sounni B, Touti R, Yamari I, et al. In silico design of pyrimidine derivatives as potential α-glucosidase inhibitors: QSAR, molecular docking, ADMET, and molecular dynamics studies. Int J Mol Sci. 2026;27 (13):5696. doi:10.3390/ijms27135696.