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List of Chronobiotics



Name SMILES FDA Status Effects Targets Mechanisms Articles
CC(C)(C)C(C)(C1CC23CCC1(C4C25CCN(C3CC6=C5C(=C(C=C6)O)O4)CC7CC7)OC)O Approved Mu opioid receptor , OPRK1 , OPRD1 opioid receptors binding Pjrek, E., Frey, R., Naderi-Heiden, A., Strnad, A., Kowarik, A., Kasper, S. and Winkler, D., 2012. Actigraphic measurements in opioid detoxification with methadone or buprenorphine. Journal of Clinical Psychopharmacology, 32(1), pp.75–82 , Gauthier, E.A., Guzick, S.E., Brummett, C.M., Baghdoyan, H.A. and Lydic, R., 2011. Buprenorphine disrupts sleep and decreases adenosine concentrations in sleep-regulating brain regions of Sprague Dawley rat. Anesthesiology, 115(4), pp.743–753.
C[N+]1(CCC(C1)OC(=O)C(C2CCCC2)(C3=CC=CC=C3)O)C.[Br-] Approved Muscarinic acetilcholine receptror M1 Affects melatonin synthesis Kärkelä, J., Vakkuri, O., Kaukinen, S., Huang, W.Q. and Pasanen, M., 2002. The influence of anaesthesia and surgery on the circadian rhythm of melatonin. Acta Anaesthesiologica Scandinavica, 46(1), pp.30–36. , Christensen, K.C., Stadil, F., Malmström, J. and Rehfeld, J.F., 1978. The effect of beta-adrenergic and cholinergic blockade on the circadian rhythm of gastrins in serum. Scandinavian Journal of Gastroenterology, 13(3), pp.263–272.
CN1CCC23C4C1CC5=C2C(=C(C=C5)OC)OC3C(C=C4)O Approved Mu opioid receptor opioid receptors binding Young, A.M., Thompson, T., Jensen, M.A. and Muchow, L.R., 1979. Effects of response-contingent clock stimuli on behavior maintained by intravenous codeine in the rhesus monkey. Pharmacology Biochemistry and Behavior, 11(1), pp.43–49. , Warfield, A.E., Prather, J.F. and Todd, W.D., 2021. Systems and circuits linking chronic pain and circadian rhythms. Frontiers in Neuroscience, 15, p.705173.
CN1CCC23C4C1CC5=C2C(=C(C=C5)O)OC3C(C=C4)O Approved Mu opioid receptor , OPRK1 , OPRD1 Unknown, opioid receptors binding Smyth, C., FitzGerald, R. and Waddington, J.L., 1995. Morphine phase-shifts circadian rhythms in mice: role of behavioural activation. Neuroreport, 7(1), pp.209–212.
CC(=O)OC1C=CC2C3CC4=C5C2(C1OC5=C(C=C4)OC(=O)C)CCN3C Not approved Mu opioid receptor , OPRK1 , OPRD1 opioid receptors binding Coffey, A.A., Guan, Z., Grigson, P.S. and Fang, J., 2016. Reversal of the sleep-wake cycle by heroin self-administration in rats. Brain Research Bulletin, 123, pp.33–46.
CC(CC1=CC=CC=C1)N Approved mPer2 , mPer1 , CLOCK-BMAL1 , Arntl (gene) Core clock modulation Wongchitrat, P., Mukda, S., Phansuwan-Pujito, P. and Govitrapong, P., 2013. Effect of amphetamine on the clock gene expression in rat striatum. Neuroscience Letters, 542, pp.126–130. , Khazaie, H., Ahmadi, H.R., Kiani, A. and Ghadami, M.R., 2019. Circadian melatonin profile in opium and amphetamine dependent patients: A preliminary study. Neurobiology of Sleep and Circadian Rhythms, 7, p.100046.
C(OC(C(F)(F)F)C(F)(F)F)F Approved mPer2 , mPer1 , CRY1-PER2 complex Core clock modulation, Unknown Kobayashi, K., Takemori, K. and Sakamoto, A., 2007. Circadian gene expression is suppressed during sevoflurane anesthesia and the suppression persists after awakening. Brain Research, 1185, pp.1–7. , Sugimura, S., Imai, R., Katoh, T., Makino, H., Hokamura, K., Kurita, T., Suzuki, Y., Aoki, Y., Kimura, T., Umemura, K. and Nakajima, Y., 2024. Effects of volatile anesthetics on circadian rhythm in mice: a comparative study of sevoflurane, desflurane, and isoflurane. Journal of Anesthesia, 38(1), pp.10–18.
C(C(F)(F)F)(OC(F)F)F Not approved CRY1-PER2 complex Core clock modulation Sugimura, S., Imai, R., Katoh, T., Makino, H., Hokamura, K., Kurita, T., Suzuki, Y., Aoki, Y., Kimura, T., Umemura, K. and Nakajima, Y., 2024. Effects of volatile anesthetics on circadian rhythm in mice: a comparative study of sevoflurane, desflurane, and isoflurane. Journal of Anesthesia, 38(1), pp.10–18. , Anzai, M., Iijima, N., Higo, S., Takumi, K., Matsuo, I., Mori, K., Ohe, Y., Kadota, K., Akimoto, T., Sakamoto, A. and Ozawa, H., 2013. Direct and specific effect of sevoflurane anesthesia on rat Per2 expression in the suprachiasmatic nucleus. PLoS One, 8(3), p.e59454.
C(C(F)(F)F)(OC(F)F)Cl Approved mPer2 , mPer1 , CRY1-PER2 complex Core clock modulation, Core clock suppression Kobayashi, K., Takemori, K. and Sakamoto, A., 2007. Circadian gene expression is suppressed during sevoflurane anesthesia and the suppression persists after awakening. Brain Research, 1185, pp.1–7. , Wren-Dail, M.A., Dauchy, R.T., Blask, D.E., Hill, S.M., Ooms, T.G., Dupepe, L.M. and Bohm, R.P. Jr., 2017. Effect of Isoflurane Anesthesia on Circadian Metabolism and Physiology in Rats. Comparative Medicine, 67(2), pp.138–146.
CN1C2CCC1CC(C2)OC(=O)C(CO)C3=CC=CC=C3 Approved ADCY1 Adenylate cyclase binding activity affects circadian clock Pérez-Llorca, M. and Müller, M., 2024. Unlocking nature’s rhythms: insights into secondary metabolite modulation by the circadian clock. International Journal of Molecular Sciences, 25(13), p.7308. , Nilsen, N.G., Gilson, S.J., Pedersen, H.R., Hagen, L.A., Wildsoet, C.F. and Baraas, R.C., 2024. The effect of topical 1% atropine on ocular dimensions and diurnal rhythms of the human eye. Vision Research, 214, p.108341.
C1CN(CC1O)CC2=CSC3=NC(=CN23)C4=CC=CC=C4NC(=O)C5=CC6=CC=CC=C6C=C5 Not approved RT2183, a SIRT1 activator, affects circadian rhythms by reducing the expression of circadian genes, achieved by decreasing the hidstone acetylation CLOCK-BMAL1 , SIRT1 SIRT1 Sultan, A., Ali, R., Sultan, T., Ali, S., Khan, N.J. and Parganiha, A., 2021. Circadian clock modulating small molecules repurposing as inhibitors of SARS-CoV-2 Mpro for pharmacological interventions in COVID-19 pandemic. Chronobiology International, 38(7), pp.971–985. , Bellet, M.M., Nakahata, Y., Boudjelal, M., Watts, E., Mossakowska, D.E., Edwards, K.A., Cervantes, M., Astarita, G., Loh, C., Ellis, J.L. and Vlasuk, G.P., 2013. Pharmacological modulation of circadian rhythms by synthetic activators of the deacetylase SIRT1. Proceedings of the National Academy of Sciences, 110(9), pp.3333-3338.
CC[C@@]1(C2=C(COC1=O)C(=O)N3CC4=CC5=CC=CC=C5N=C4C3=C2)O Not approved lengthening of the circadian period, as Bmal1 is involved in determining the length of the clock's oscillation. CLOCK-BMAL1 Bmal1 Raju, U., Koumenis, C., Nunez-Regueiro, M. and Eskin, A., 1991. Alteration of the phase and period of a circadian oscillator by a reversible transcription inhibitor. Science, 253(5020), pp.673-675.
C1CN(CCN1)CC2=CSC3=NC(=CN23)C4=CC=CC=C4NC(=O)C5=NC6=CC=CC=C6N=C5.Cl Not approved Studies using SRT1720 have demonstrated that it can alter the expression of genes involved in the circadian clock. CLOCK-BMAL1 , SIRT1 Core clock modulation Bellet, M.M., Nakahata, Y., Boudjelal, M., Watts, E., Mossakowska, D.E., Edwards, K.A., Cervantes, M., Astarita, G., Loh, C., Ellis, J.L., Vlasuk, G.P. and Sassone-Corsi, P., 2013. Pharmacological modulation of circadian rhythms by synthetic activators of the deacetylase SIRT1. Proceedings of the National Academy of Sciences of the United States of America, 110(9), pp.3333–3338. , Yao, H., Sundar, I.K., Huang, Y., Gerloff, J., Sellix, M.T., Sime, P.J. and Rahman, I., 2015. Disruption of sirtuin 1–mediated control of circadian molecular clock and inflammation in chronic obstructive pulmonary disease. American journal of respiratory cell and molecular biology, 53(6), pp.782-792.
CC1=NC=CC2=C1NC3=C2C=CC(=C3)OC Not approved lengthen the circadian period, meaning the time it takes for the clock to complete one cycle, Specifically, it can increase the stability of PER2 protein, a key player in the molecular clock, and enhance the function of RORα, another protein in CLOCK-BMAL1 , RORα Bmal1 Onishi, Y., Oishi, K., Kawano, Y. and Yamazaki, Y., 2012. The harmala alkaloid harmine is a modulator of circadian Bmal1 transcription. Bioscience Reports, 32(1), pp.45-52. , Kondoh, D., Yamamoto, S., Tomita, T., Miyazaki, K., Itoh, N., Yasumoto, Y., Oike, H., Doi, R. and Oishi, K., 2014. Harmine lengthens circadian period of the mammalian molecular clock in the suprachiasmatic nucleus. Biological and Pharmaceutical Bulletin, 37(8), pp.1422-1427.
CC(=O)N1CCN(CC1)CC2=CC=C(C=C2)C3=CC=C(C=C3)C(C(F)(F)F)(C(F)(F)F)O Not approved Suppresses TH17 cells and Stimulates T Regulatory Cells, It reduces food intake, fat mass, and improves insulin sensitivity in obese diabetic mice, indicating potential as an anti-diabetic and anti-obesity RORα ROR Xiang, K., Xu, Z., Hu, Y.Q., He, Y.S., Wu, G.C., Li, T.Y., Wang, X.R., Ding, L.H., Zhang, Q., Tao, S.S. and Ye, D.Q., 2021. Circadian clock genes as promising therapeutic targets for autoimmune diseases. Autoimmunity Reviews, 20(8), p.102866. , Chang, M.R., He, Y., Khan, T.M., Kuruvilla, D.S., Garcia-Ordonez, R., Corzo, C.A., Unger, T.J., White, D.W., Khan, S., Lin, L. and Cameron, M.D., 2015. Antiobesity effect of a small molecule repressor of RORγ. Molecular Pharmacology, 88(1), pp.48-56. , Solt, L.A., Kumar, N., He, Y., Kamenecka, T.M., Griffin, P.R. and Burris, T.P., 2012. Identification of a selective RORγ ligand that suppresses TH17 cells and stimulates T regulatory cells. ACS chemical biology, 7(9), pp.1515-1519.
CC1CC(CN(C1)C(=O)CC(C2=CC3=C(C=C2)OCO3)C4=C(C=C(C=C4OC)OC)O)C Not approved inhibited the transcriptional activity of RORγt RORα ROR Huang, W., Wang, H., Johnson, R.L., Huang, R., Englund, E.E., Huh, J. and Littman, D.R., 2013. Identification of potent and selective RORγ antagonists. Probe Reports from the NIH Molecular Libraries Program [Internet].
C1CN(CCN1CC2=CC=C(C=C2)C3=C(C=C(C=C3)C(C(F)(F)F)(C(F)(F)F)O)F)CC4=CC=NC=C4 Not approved SR2211 acts as an inverse agonist of RORγ, meaning it blocks the activity of the receptor. This can have implications for circadian rhythms, as RORγ's RORα ROR Kumar, N., Lyda, B., Chang, M.R., Lauer, J.L., Solt, L.A., Burris, T.P., Kamenecka, T.M. and Griffin, P.R., 2012. Identification of SR2211: a potent synthetic RORγ-selective modulator. ACS chemical biology, 7(4), pp.672-677.
CC1=C(SC(=N1)NC(=O)C)S(=O)(=O)NC2=CC=C(C=C2)C(C(F)(F)F)(C(F)(F)F)O Not approved resets the molecular circadian clock in eosinophils RORα ROR Ribeiro, R.F., Cavadas, C. and Silva, M.M.C., 2021. Small-molecule modulators of the circadian clock: Pharmacological potentials in circadian-related diseases. Drug Discovery Today, 26(7), pp.1620-1641. , Teppan, J., Bärnthaler, T., Farzi, A., Durrington, H., Gioan-Tavernier, G., Platt, H., Wolf, P., Heinemann, A. and Böhm, E., 2025. The molecular circadian clock of eosinophils: A potential therapeutic target for asthma. American Journal of Physiology-Cell Physiology, 328(5), pp.C1394-C1408.
C1=CSC(=C1)S(=O)(=O)NC2=CC=C(C=C2)C(C(F)(F)F)(C(F)(F)F)O Not approved leading to a decrease in the expression of core clock genes, which are essential for maintaining circadian rhythms. This can affect various aspects of RORα ROR Kumar, N., Kojetin, D.J., Solt, L.A., Kumar, K.G., Nuhant, P., Duckett, D.R., Cameron, M.D., Butler, A.A., Roush, W.R., Griffin, P.R. and Burris, T.P., 2011. Identification of SR3335 (ML-176): a synthetic RORα selective inverse agonist. ACS chemical biology, 6(3), pp.218-222.
TH301 Not approved CRY1-PER2 complex Selectively stabilizes CRY2 Miller, S., Son, Y.L., Aikawa, Y., Makino, E., Nagai, Y., Srivastava, A., Oshima, T., Sugiyama, A., Hara, A., Abe, K. and Hirata, K., 2020. Isoform-selective regulation of mammalian cryptochromes. Nature chemical biology, 16(6), pp.676-685.
CC1=CC(=C(C=C1)N2C(=C3CSCC3=N2)NC(=O)C4=CC(=C(C=C4)C)C)C Not approved CRY1 Selective stabilizer of CRY1 Miller, S., Son, Y.L., Aikawa, Y., Makino, E., Nagai, Y., Srivastava, A., Oshima, T., Sugiyama, A., Hara, A., Abe, K. and Hirata, K., 2020. Isoform-selective regulation of mammalian cryptochromes. Nature chemical biology, 16(6), pp.676-685.
C1CCC2=C(C1)C3=C(N=CN=C3S2)NC(=O)C4=CC=CC=C4Br Not approved lengthen circadian rhtyhms CRY1 Selective stabilizer of CRY1 Crane, B.R., 2020. Winding down: Selectively drugging a promiscuous pocket in cryptochrome slows circadian rhythms. Cell chemical biology, 27(9), pp.1109-1111.
CCS(=O)(=O)C1=CC=C(C=C1)CC(=O)NC2=CC(=C(C(=C2)Cl)C3=CC=CC=C3OC(F)(F)F)Cl Not approved Disrupts cellular circadian system RORα ROR Borrmann, H., Ulkar, G., Kliszczak, A.E., Ismed, D., Schilling, M., Magri, A., Harris, J.M., Balfe, P., Vasudevan, S., Borrow, P. and Zhuang, X., 2023. Molecular components of the circadian clock regulate HIV-1 replication. Iscience, 26(7).
CC1CC(C(C(C=C(C(C(C=CC=C(C(=O)NC2=CC(=O)C=C(C1OC)C2=O)C)OC)OC(=O)N)C)C)OC)OC Approved CLOCK-BMAL1 Core clock modulation Davis, M.A. and Carbott, D.E., 1999. Herbimycin A and geldanamycin inhibit okadaic acid-induced apoptosis and p38 activation in NRK-52E renal epithelial cells. Toxicology and applied pharmacology, 161(1), pp.59-74. , Zhang, Z., Xue, N., Bian, C., Yan, R., Jin, L., Chen, X. and Yu, X., 2016. C15-methoxyphenylated 18-deoxy-herbimycin A analogues, their in vitro anticancer activity and heat shock protein 90 binding affinity. Bioorganic & Medicinal Chemistry Letters, 26(17), pp.4287-4291.
CC1CC(C(C(C=C(C(C(C=CC=C(C(=O)NC2=CC(=O)C(=C(C1)C2=O)OC)C)OC)OC(=O)N)C)C)O)OC Not approved heat shock protein 90 binding affinity affectin circadian clock (indirect effects CLOCK-BMAL1 HSP90 binding (in Arabidopsis) Davis, M.A. and Carbott, D.E., 1999. Herbimycin A and geldanamycin inhibit okadaic acid-induced apoptosis and p38 activation in NRK-52E renal epithelial cells. Toxicology and applied pharmacology, 161(1), pp.59-74.