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List of Chronobiotics



Name SMILES FDA Status Effects Targets Mechanisms Articles
Unknown None GUT MICROBIOTA Unknown metabolites
C1=CC=C2C(=C1)C(=C(N2)O)C3=NC4=CC=CC=C4C3=O none period shortening of the mammalian circadian clock by specific inhibition of GSK-3β GSK-3α/β Highly selective, ATP-competitive inhibition of GSK-3 (both α and β isoforms), Dual inhibitor of Cyclin-dependent kinases (CDK) and Glycogen Synthase Kinase-3 (GSK-3), GSK‑3 Inhibition, Selective GSK-3β Inhibition:, inhibits glycogen synthase kinase-3β (GSK-3β) Hirota, T., Lewis, W.G., Liu, A.C., Lee, J.W., Schultz, P.G. and Kay, S.A., 2008. A chemical biology approach reveals period shortening of the mammalian circadian clock by specific inhibition of GSK-3β. Proceedings of the National Academy of Sciences, 105(52), pp.20746-20751.
C1CCC(CC1)N2C=NC(=C2C3=NC(=NC=C3)N)C4=CC=C(C=C4)F.Cl. Cl None CKI delta Inhibits CK1δ, Inhibits casein kinase 1 delta (CKIδ) activity, Non-specific kinase inhibitor Wagner, P.M., Fornasier, S.J. and Guido, M.E., 2024. Pharmacological modulation of the cytosolic oscillator affects glioblastoma cell biology. Cellular and Molecular Neurobiology, 44(1), p.51.
[Li+].[Li+].C(=O)([O-])[O-] Approved mPer2 , mPer1 , CRY1-PER2 complex , CRY1 , CRY1 , Per2 expression inhibits glycogen synthase kinase-3β (GSK-3β) Rohr, K.E. and McCarthy, M.J., 2022. The impact of lithium on circadian rhythms and implications for bipolar disorder pharmacotherapy. Neuroscience letters, 786, p.136772.
CS(=O)C1=CC=C(C=C1)C2=NC(=C(N2)C3=CC=NC=C3)C4=CC=C(C=C4)F None p38 kinase Core clock modulation, p38 signaling
COC1=C(N=CC(=C1OC)N2C(=O)N(C3=C(S2(=O)=O)C=CC=N3)CC4=C(C=C(C=C4F)F)F Not approved primarily affect circadian rhythms by promoting sleep, particularly reducing wakefulness after sleep onset and improving sleep maintenance orexin receptor subtypes (OX1 and OX2) Dopamine receptor antagonist, Orexin Receptor Antagonism Christopher, J.A., Aves, S.J., Brown, J., Errey, J.C., Klair, S.S., Langmead, C.J., Mace, O.J., Mould, R., Patel, J.C., Tehan, B.G. and Zhukov, A., 2015. Discovery of HTL6641, a dual orexin receptor antagonist with differentiated pharmacodynamic properties. MedChemComm, 6(5), pp.947-955.
C[C@@H]1CC(=O)C=C([C@]12C(=O)C3=C(O2)C(=C(C=C3OC)OC)Cl)OC Approved ~0.3 h shortening of the period of circadian T(b) rhythms in mice kept under conditions of constant darkness (P < 0.01) CLOCK-BMAL1 , Heme Core clock modulation, Affects heme, Affects heme biosynthesis Iwadate, R., Satoh, Y., Watanabe, Y., Kawai, H., Kudo, N., Kawashima, Y., Mashino, T. and Mitsumoto, A., 2012. Impairment of heme biosynthesis induces short circadian period in body temperature rhythms in mice. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 303(1), pp.R8-R18.
C1=CC2=C(C=C1O)C(=O)OC3=C2C=CC(=C3)O Not approved Arntl (gene) , BMAL1 expression (induction) , Per2 expression , GUT MICROBIOTA Bmal1, de-repressing BMAL1, BMAL1 expression modulation, BMAL1 expression modulation, Activation of CLOCK/Bmal1 mediated transcription Du, Y., Chen, X., Kajiwara, S. and Orihara, K., 2024. Effect of Urolithin A on the Improvement of Circadian Rhythm Dysregulation in Intestinal Barrier Induced by Inflammation. Nutrients, 16(14), p.2263.
Lactobacillus delbrueckii none restores normal circadian rhythms, improves circadian rhythms in pigs GUT MICROBIOTA protect, Circadian Clock Impact, Unknown metabolites Luo, W., Yin, Z., Zhang, M., Huang, X. and Yin, J., 2024. Dietary Lactobacillus delbrueckii Affects Ileal Bacterial Composition and Circadian Rhythms in Pigs. Animals, 14(3), p.412.
CC12CC(C3(C(C1CC(C2(C(=O)CO)O)O)CCC4=CC(=O)C=CC43C)F)O Approved alters the circadian rhythm Corticosteroid hormone receptor Core clock modulation, Affects "Circadian rhtyhm signaling", Calcium signaling, Glutamat receptor signaling, Corticosteroid Hormone Receptor Agonist Smit-McBride, Z., Moisseiev, E., Modjtahedi, S.P., Telander, D.G., Hjelmeland, L.M. and Morse, L.S., 2016. Comparison of in vivo gene expression profiling of RPE/choroid following intravitreal injection of dexamethasone and triamcinolone acetonide. Journal of Ophthalmology, 2016(1), p.9856736.
COC(=O)N1CCC[C@@H]([C@@H]1COC2CCC(CC2)C3=CC=CC=C3)NS(=O)(=O)C Not approved improve wakefulness in individuals with certain sleep disorders orexin receptor subtypes (OX1 and OX2) OX₂R Activation Yin, J., Kang, Y., McGrath, A.P., Chapman, K., Sjodt, M., Kimura, E., Okabe, A., Koike, T., Miyanohana, Y., Shimizu, Y. and Rallabandi, R., 2022. Molecular mechanism of the wake-promoting agent TAK-925. Nature communications, 13(1), p.2902.
CC1=NC2=C(O1)C=C(C=C2)NC(=O)NC3=C4C(=NC=C3)C=CC=N4 Not approved can attenuate the sleep-promoting effects of the OX2R antagonist orexin receptor subtypes (OX1 and OX2) OX₁R Antagonism Morairty, S.R., Revel, F.G., Malherbe, P., Moreau, J.L., Valladao, D., Wettstein, J.G., Kilduff, T.S. and Borroni, E., 2012. Dual hypocretin receptor antagonism is more effective for sleep promotion than antagonism of either receptor alone. PloS one, 7(7), p.e39131.
C[C@H]1CC[C@H](N(C1)C(=O)C2=C(C(=CC=C2)F)OC)CNC3=NC=C(C=C3)Br Not approved sleep-promoting effects orexin receptor subtypes (OX1 and OX2) OX₁ Receptor Blockade Aluisio, L., Fraser, I., Berdyyeva, T., Tryputsen, V., Shireman, B.T., Shoblock, J., Lovenberg, T., Dugovic, C. and Bonaventure, P., 2014. Pharmacological or genetic orexin1 receptor inhibition attenuates MK-801 induced glutamate release in mouse cortex. Frontiers in neuroscience, 8, p.107.
Clc1ccc(c(c1)Br)CNc1cccc(c1)c1nnc[nH]1 None phase advance, lengthened the periods of BMAL1 and PER2 MT1 MT1 receptor binding Stein, R.M., Kang, H.J., McCorvy, J.D., Glatfelter, G.C., Jones, A.J., Che, T., Slocum, S., Huang, X.P., Savych, O., Moroz, Y.S. and Stauch, B., 2020. Virtual discovery of melatonin receptor ligands to modulate circadian rhythms. Nature, 579(7800), pp.609-614.
C[C@]12CCC(=O)C=C1CC[C@@H]3[C@@H]2[C@H](C[C@]4([C@H]3CC[C@@]4(C(=O)CO)O)C)O Approved Corticosteroid hormone receptor Glucocorticoid Signaling, Glucocorticoid receptors Kanki, M. and Young, M.J., 2021. Corticosteroids and circadian rhythms in the cardiovascular system. Current Opinion in Pharmacology, 57, pp.21-27.
CC12CCC(=O)C=C1CCC3C2C(CC4(C3CCC4C(=O)CO)C=O)O Approved Aldosterone influences the expression of clock genes such as Per1, Per2, and Bmal1 in cardiomyoblasts mPer2 , mPer1 , Arntl (gene) , BMAL1 expression (induction) PER gene exspression modulation, BMAL1 expression modulation, BMAL1 expression modulation, Activation of CLOCK/Bmal1 mediated transcription, influences HPA axis Tanaka, K., Ashizawa, N., Kawano, H., Sato, O., Seto, S., Nishihara, E., Terazono, H., Isomoto, S., Shinohara, K. and Yano, K., 2007. Aldosterone induces circadian gene expression of clock genes in H9c2 cardiomyoblasts. Heart and vessels, 22, pp.254-260.
CN1C2=C(C(=O)N(C1=O)C)NC=N2 Approved cause period lengthening in a concentration-dependent manner PI3K/Akt , NF-kB Nuclear Factor Kappa B (NF- κB), cAMP signaling cascade, Modulation of PI3K/Akt Ehret, C.F., Potter, V.R. and Dobra, K.W., 1975. Chronotypic action of theophylline and of pentobarbital as circadian zeitgebers in the rat. Science, 188(4194), pp.1212-1215. , Szarłowicz, J., Mazur, M., Waz, D., Goliszek, Z., Sobek, K.Ł., Tabin-Barczak, W., Sokołowska, A., Fikas, K., Chwaliszewski, K. and Samuła, S., 2025. Theophylline Revisited. Mechanisms, Challenges, and New Horizons. Quality in Sport, 37, pp.57009-57009. , Olivares-Yañez, C., Alessandri, M.P., Salas, L. and Larrondo, L.F., 2023. Methylxanthines modulate circadian period length independently of the action of phosphodiesterase. Microbiology Spectrum, 11(4), pp.e03727-22.
CN(C)CCC1=CNC2=C1C(=CC=C2)O Not approved led to delayed REM sleep onset and reduced NREM sleep maintenance for up to approximately 3 h after dosing, is a rapidly-emerging treatment for depression 5-HT 2A R Serotoninergic signaling, Dopamine receptor binding Thomas, C.W., Blanco-Duque, C., Bréant, B.J., Goodwin, G.M., Sharp, T., Bannerman, D.M. and Vyazovskiy, V.V., 2022. Psilocin acutely alters sleep-wake architecture and cortical brain activity in laboratory mice. Translational psychiatry, 12(1), p.77. , Reid, M.J., Kettner, H., Blanken, T.F., Weiss, B. and Carhartt-Harris, R., 2024. Preliminary Evidence of Sleep Improvements Following Psilocybin Administration, and their Involvement in Antidepressant Therapeutic Action. Current psychiatry reports, pp.1-11.
CCC1=C2C=COC2=C(OCCCO)C=C1 none directly targets BMAL1, impacting its ability to regulate gene expression within the circadian clock and immune system CLOCK-BMAL1 , BMAL1 Core clock modulation, Bmal1 Zeng, Y., Guo, Z., Wu, M., Chen, F. and Chen, L., 2024. Circadian rhythm regulates the function of immune cells and participates in the development of tumors. Cell death discovery, 10(1), p.199. , Pu, H., Bailey, L.C., Bauer, L.G., Voronkov, M., Baxter, M., Huber, K.V., Khorasanizadeh, S., Ray, D. and Rastinejad, F., 2025. Pharmacological targeting of BMAL1 modulates circadian and immune pathways. Nature Chemical Biology, pp.1-10.
C1=CC(=C2C(=C1)C=CO2)OCCCO none directly targets BMAL1, impacting its ability to regulate gene expression within the circadian clock and immune system CLOCK-BMAL1 , BMAL1 Bmal1, Activation of CLOCK/Bmal1 mediated transcription, Interferes with CLOCK–BMAL1, Targets BMAL1–CLOCK DNA-binding activity Pu, H., Bailey, L.C., Bauer, L.G., Voronkov, M., Baxter, M., Huber, K.V., Khorasanizadeh, S., Ray, D. and Rastinejad, F., 2025. Pharmacological targeting of BMAL1 modulates circadian and immune pathways. Nature Chemical Biology, pp.1-10.
CC1(C)CC2=C(CO)C3=C(COC3=O)C(=C2C1)O None Advances circadian rhtyhms mPer2 , Per2 expression Core clock modulation, Binding with factors affine to Period2 gene promoter Kobayashi, Y., Lu, Y., Li, N., Endo, N., Sotome, K., Ueno, K., Tahara, Y. and Ishihara, A., 2024. A new phthalide derivative from the mushroom Cyclocybe cf. erebia culture filtrate affects the phase of circadian rhythms in mouse fibroblasts. Bioscience, Biotechnology, and Biochemistry, p.zbae187.
COC1=C(C=CC(=C1)C2=CC(=O)C3=C(C(=C(C(=C3O2)OC)O)OC)O)O none restores normal circadian rhythms CLOCK-BMAL1 , BMAL1 expression (induction) Core clock modulation, Bmal1, de-repressing BMAL1, BMAL1 expression modulation, BMAL1 expression modulation, Activation of CLOCK/Bmal1 mediated transcription Mawatari, K., Koike, N., Nohara, K., Wirianto, M., Uebanso, T., Shimohata, T., Shikishima, Y., Miura, H., Nii, Y., Burish, M.J. and Yagita, K., 2023. The polymethoxyflavone sudachitin modulates the circadian clock and improves liver physiology. Molecular Nutrition & Food Research, 67(9), p.2200270.
C1=CC=C(C=C1)C(C2=CC=CC=C2)S(=O)CC(=O)N Approved dose dependently increases wakefulness at the expense of slow-wave and paradoxical sleep with no increase in locomotor activity per unit of time awake DAT ( human Dopamine transporter) DAT interaction (human dopamine transporter) Kim, D., 2012. Practical use and risk of modafinil, a novel waking drug. Environmental health and toxicology, 27, p.e2012007. , Webb, I.C., Pollock, M.S. and Mistlberger, R.E., 2006. Modafinil [2-[(diphenylmethyl) sulfinyl] acetamide] and circadian rhythms in syrian hamsters: assessment of the chronobiotic potential of a novel alerting compound. The Journal of pharmacology and experimental therapeutics, 317(2), pp.882-889. , Uyhelji, H.A., Munster, S.K., White, V.L. and Nicholson, S.J., 2023. Gene expression biomarkers of the response to sleep loss with and without modafinil (No. DOT/FAA/AM-23/25). United States. Department of Transportation. Federal Aviation Administration. Office of Aviation. Civil Aerospace Medical Institute.
C1=CC2=C(C=C1F)C3=C(C=CC(=C3)F)N2C[C@H](CN4CCNC4=O)O none disrupts the circadian clock specifically in cancer cells, disrupts glioblastoma clock CRY2 , Mouse CRY2 with shp656 Selectively stabilizes CRY2 Miller, S., Kesherwani, M., Chan, P., Nagai, Y., Yagi, M., Cope, J., Tama, F., Kay, S.A. and Hirota, T., 2022. CRY2 isoform selectivity of a circadian clock modulator with antiglioblastoma efficacy. Proceedings of the National Academy of Sciences, 119(40), p.e2203936119.
C1=CC2=C(C=C1F)C3=C(C=CC(=C3)F)N2CC(CN4CCNC4=O)O None disrupts glioblastoma clock CRY2 , Mouse CRY2 with shp656 Selectively stabilizes CRY2 Miller, S., Kesherwani, M., Chan, P., Nagai, Y., Yagi, M., Cope, J., Tama, F., Kay, S.A. and Hirota, T., 2022. CRY2 isoform selectivity of a circadian clock modulator with antiglioblastoma efficacy. Proceedings of the National Academy of Sciences, 119(40), p.e2203936119.