Larvicidal Activities of 2-Aryl-2,3-Dihydroquinazolin -4-ones against Malaria Vector Anopheles arabiensis, In Silico ADMET Prediction and Molecular Target Investigation
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Crystallography
Crystal Structure Analysis of 2-(3,4-Dimethoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (3g)
2.3. Larvicidal Activity
2.4. In Silico Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) Analysis
2.5. Molecular Modeling
3. Materials and Methods
3.1. General
3.2. General Procedure for the Synthesis of 2-(Substituted phenyl)-2,3-dihydroquinazolin-4(1H)-ones (3a–n)
3.2.1. 2-(4-Methoxyphenyl)-2, 3-dihydroquinazolin-4(1H)-one (3a)
3.2.2. 4-(4-Oxo-1,2,3,4-tetrahydroquinazolin-2-yl)benzonitrile (3b)
3.2.3. 2-(3-Hydroxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (3c)
3.2.4. 2-(4-(Trifluoromethoxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one (3d)
3.2.5. 2-(3-Iodophenyl)-2,3-dihydroquinazolin-4(1H)-one (3e)
3.2.6. 2-(4-Chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (3f)
3.2.7. 2-(3,4-Dimethoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (3g)
3.2.8. 2-(4-(Dimethylamino)phenyl)-2,3-dihydroquinazolin-4(1H)-one (3h)
3.2.9. 2-(3-Nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (3i)
3.2.10. 2-(4-Fluorophenyl)-2,3-dihydroquinazolin-4(1H)-one (3j)
3.2.11. 2-(1H-Imidazol-4-yl)-2,3-dihydroquinazolin-4(1H)-one (3k)
3.2.12. 2-(2-Methoxy-4-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (3l)
3.2.13. 2-(2-Hydroxy-5-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (3m)
3.2.14. 2-(4-Hydroxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (3n)
3.3. Crystallographic Studies
3.4. Larvicidal Activity
3.5. Data Analysis
3.6. In silico ADMET Prediction
3.7. Molecular Modeling
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Sample Availability: Samples of the compounds 3a–n are available from the authors. |
Compound Code | Ar | Molecular Formula (Molecular Mass) | Yield (%) | m.p (°C) Reported | mp (°C) Found | cLogP | References | CAS Number |
---|---|---|---|---|---|---|---|---|
3a | 4-OCH3-Ph | C15H14N2O2 (254) | 95 | 182–183 | 181–182 | 2.2388 | [45] | 61195-16-2 |
3b | 4-CN-Ph | C15H11N3O (249) | 92 | 178–180 | 178–180 | 1.7528 | [44] | 219619-59-7 |
3c | 3-OH-Ph | C14H12N2O2 (240) | 91 | 184–186 | 185–187 | 1.6528 | [46] | 107922-06-5 |
3d | 4-OCF3-Ph | C15H11F3N2O2 (308) | 94 | 194–196 | 195–196 | 3.3478 | [47] | 685505-75-3 |
3e | 3-I-Ph | C14H11IN2O (349) | 92 | -- | 153–155 | 3.4428 | Novel Compound | |
3f | 4-Cl-Ph | C14H11ClN2O (258) | 87 | 197–198 | 198–199 | 3.0328 | [44] | 13165-11-2 |
3g | 3,4-diOCH3-Ph | C16H16N2O3 (284) | 88 | 214–216 | 213–215 | 1.9778 | [46] | 126492-17-9 |
3h | 4-N,N dimethyl-Ph | C16H17N3O (267) | 93 | 209–211 | 210–211 | 2.4848 | [48] | 66181-66-6 |
3i | 3-NO2-Ph | C14H11N3O3 (269) | 91 | 192–194 | 192–1193 | 2.0628 | [44] | 26029-30-1 |
3j | 4-F-Ph | C14H11FN2O (242) | 91 | 196–198 | 197–198 | 2.4628 | [48] | 359605-44-0 |
3k | Imidazole | C11H10N4O (214) | 87 | -- | 156–158 | 0.1488 | Novel Compound | |
3l | 2-OCH3-4-NO2-Ph | C15H13N3O4 (299) | 93 | -- | 149–151 | 2.2818 | Novel Compound | |
3m | 2-OH, 5-NO2-Ph | C14H11N3O4 (285) | 89 | 244–246 | 245–246 | 1.9818 | [49] | 1794721-69-9 |
3n | 4-OH-Ph | C14H12N2O2 (240) | 95 | 209–211 | 210–211 | 1.6528 | [50] | 107920-18-3 |
CCDC Number | 1983734 |
---|---|
Molecular Formula | C16H16N2O3 |
Molecular weight | 284.31 |
Temperature | 173(2) |
Crystal Size (mm) | 0.2, 0.110, 0.040 |
Absorption coefficient (mm−1) | 0.096 |
Tmin, Tmax | 0.981, 0.996 |
Crystal system | Monoclinic |
Lattice parameters: a (Å), b (Å), c (Å) | 7.8881(6), 20.2194 (13), 8.9638 (6) |
α, β, γ (°) | 90, 104.887(3), 90 |
Space Group, Density, Z, Z′ | P21/n, 1.367, 4, 1 |
hmin, max; kmin, max; lmin, max; | −8, 10; −26, 26; −11, 11 |
Number of total/unique/observed reflections | 13,538, 3403, 2321 |
No. of parameters | 200 |
Independent reflections, Rint | 3403, 0.0482 |
Rall, Robs | 0.0879, 0.0544 |
wR2all, wR2obs | 0.1425, 0.1221 |
Δρmax, min (eÅ−3) | 0.541, −0.269 |
goodness-of-fit (G.o.F) | 1.029 |
Interaction | H···A (Å) | D···A (Å) | ∠D–H···A (°) | Symmetry Code |
---|---|---|---|---|
N1–H1···O2 | 2.30 | 3.176 | 170 | −x + 1, −y, −z + 2 |
N2–H2···O3 | 2.30 | 3.070 | 148 | −x, −y, −z + 2 |
C16–H16C···O1 | 2.66 | 3.441 | 137 | −x, −y, −z + 2 |
C3–H3···O1 | 2.54 | 3.167 | 124 | x + 1,+y,+z |
C2–H2C···O1 | 2.57 | 3.180 | 122 | x + 1,+y,+z |
C2–H2C···O3 | 2.64 | 3.421 | 140 | −x + 1, −y, −z + 2 |
Compound | 24-h Mortality | 48-h Mortality |
---|---|---|
3a (4-OCH3) | 0.77 ± 0.04 d,e,f | 0.83 ± 0.04 c,d,e |
3b (4-CN) | 0.86 ± 0.04 b,c,d,e | 0.88 ± 0.03 b,c,d |
3c (3-OH) | 0.51 ± 0.05 h,i,j,k,l,m | 0.57 ± 0.05 h,i,j,k,l |
3d (4-OCF3) | 0.91 ± 0.03 b,c | 0.93 ± 0.03 a,b |
3e (3-I) | 0.82 ± 0.04 c,d,e | 0.87 ± 0.04 b,c,d |
3f (4-Cl) | 0.87 ± 0.04 b,c,d | 0.91 ± 0.03 b,c |
3g (3,4-diOCH3) | 0.62 ± 0.05 g,h,i,j | 0.66 ± 0.05 f,g,h |
3h (4-N(CH3)2) | 0.41 ± 0.05 m | 0.43 ± 0.05 l,m |
3i (3-NO2) | 0.52 ± 0.05 h,i,j,k,l,m | 0.54 ± 0.05 h,i,j,k,l,m |
3j (4-F) | 0.89 ± 0.03 b,c | 0.91 ± 0.03 b,c |
3k (imidazole) | 0.46 ± 0.05 k,l,m | 0.48 ± 0.05 j,k,l,m |
3l (2-OCH3, 4-NO2) | 0.74 ± 0.05 e,f,g | 0.77 ± 0.04 d,e,f |
3m (2-OH, 5-NO2) | 0.59 ± 0.05 h,i,j,k | 0.64 ± 0.05 f,g,h,i |
3n (4-OH) | 0.50 ± 0.05 i,j,k,l,m | 0.52 ± 0.05 h,i,j,k,l,m |
Temephos | 0.99 ± 0.01 a | 1.00 ± 0.00 a |
Acetone | 0.01 ± 0.01 m | 0.04 ± 0.02 n |
Entry | Solubility Level | Blood–Brain Barrier Penetration (BBB) Level | CYP450 Inhibition | Hepatotoxicity | Intestinal Absorption Level | Plasma Protein Binding | AlogP | PSA 2D |
---|---|---|---|---|---|---|---|---|
Temephos | 2 | 0 | - | + | 0 | + | 5.656 | 53.58 |
3a (4-OCH3) | 3 | 2 | - | + | 0 | + | 2.432 | 51.851 |
3b (4-CN) | 3 | 2 | - | + | 0 | + | 2.327 | 65.856 |
3c (3-OH) | 3 | 2 | - | + | 0 | + | 2.206 | 63.736 |
3d (4-OCF3) | 1 | 1 | - | + | 0 | + | 4.568 | 51.851 |
3e (3-I) | 2 | 1 | - | + | 0 | + | 3.026 | 42.921 |
3f (4-Cl) | 2 | 1 | - | + | 0 | + | 3.113 | 42.921 |
3g (3,4-diOCH3) | 3 | 2 | - | + | 0 | + | 2.415 | 60.781 |
3h (4-N(CH3)2) | 3 | 2 | - | + | 0 | + | 2.610 | 46.273 |
3i (3-NO2) | 3 | 3 | - | + | 0 | + | 2.343 | 85.744 |
3j (4-F) | 3 | 2 | - | + | 0 | + | 2.654 | 42.921 |
3k (imidazole) | 4 | 3 | - | + | 0 | - | 0.632 | 69.237 |
3l (2-OCH3, 4-NO2) | 3 | 2 | - | + | 0 | + | 2.326 | 94.674 |
3m (2-OH, 5-NO2) | 3 | 3 | - | + | 0 | + | 2.101 | 106.559 |
3n (4-OH) | 3 | 2 | - | + | 0 | + | 2.206 | 63.736 |
Entry | Larvicidal Activity | Stereoisomer | Binding Energy (kJ/mol) | Residues Interaction | |
---|---|---|---|---|---|
H-Bond (Interacting Atom) | Hydrophobic (π–π) | ||||
Native ligand | - | - | −46.68 | Ser 280, Tyr 282 | Gly 279, Trp 285, Tyr 489 |
Temephos | - | - | 0 | - | - |
3a (4-OCH3) | 0.77 | R | −93.21 | Trp 245 (NH), Tyr 489 (NHCO) | Trp 245, His 600 |
S | −114.50 | Gly 279 (NHCO), Ser 280 (NHCO) Tyr 489 (NH) | Tyr 282, Trp 245, Tyr 489 | ||
3b (4-CN) | 0.86 | R | −98.03 | Ser 283 (NHCO), Tyr 489 (NH) Tyr 291 (CN) | Trp 245, Tyr 282, Asp 233 (ion-pi) |
S | −81.74 | Trp 245 (NH), Tyr 291 (CN) Gly 278 (CN), Tyr 282 (NHCO) Tyr 489 (NHCO) | Trp 245 | ||
3c (3-OH) | 0.51 | R | −99.16 | Ser 289 (NHCO), Tyr 291 (OH) Glu 359 (OH) | Trp 245, Tyr 489 |
S | −89.42 | Ser 280 (OH), Tyr 282 (OH) Ser 283 (NHCO), Tyr 289 (NH) | Trp 245, Tyr 489 | ||
3d (4-OCF3) | 0.91 | R | −110.82 | Gly 278 (CF3), Tyr 291 (CF3) Tyr 489 (NH) | Trp 245, Tyr 282, Asp 233 (ion-pi), Glu 359 (F), Gly 278 (F) |
S | −106.47 | Ser 283 (NHCO) Tyr 489 (NH) | Trp 245, Tyr 282, Tyr 489 | ||
3e (3-I) | 0.82 | R | −105.04 | Tyr 489 (NH) | Trp 245, Tyr 282, Tyr 489, Asn 246 (I) |
S | −75.88 | Trp 245 (NH) | Trp 245 | ||
3f (4-Cl) | 0.87 | R | −108.19 | Ser 283 (NHCO) Tyr 489 (NH) | Tyr 282, Trp 245, Asp 233 (ion-pi) |
S | −81.59 | Trp 245 (NH), Tyr 282 (NHCO) Tyr 489 (NHCO), Glu 359 (Cl) | Tyr 245 | ||
3g (3,4-diOCH3) | 0.62 | R | −95.90 | Ser 283 (NHCO) Tyr 489 (NH) | Trp 245, Tyr 282, Tyr 489 |
S | −91.29 | Trp 245 (NH), Tyr 282 (NHCO) Tyr 489 (NHCO) | Tyr 245 | ||
3h (4-N(CH3)2) | 0.41 | R | −92.98 | Tyr 489 (NH) | Trp 245, Tyr 282, Tyr 489 |
S | −91.01 | Ser 283 (NHCO) Tyr 489 (NH) | Trp 245, Tyr 489 | ||
3i (3-NO2) | 0.52 | R | −108.38 | Asp 233 (NO2), Ser 283 (NHCO) Tyr 489 (NH) | Trp 245, Tyr 282, Tyr 489 |
S | −131.24 | Ser 280 (NHCO) Tyr 489 (NH) | Trp 245, Tyr 282 | ||
3j (4-F) | 0.89 | R | −101.15 | Ser 283 (NHCO) Tyr 489 (NH) | Trp 245, Tyr 489 |
S | −76.85 | Tyr 291 (NHCO) Tyr 489 (NH) | Trp 245, Tyr 489 | ||
3k (imidazole) | 0.46 | R | −91.64 | Ser 283 (NHCO) Tyr 489 (NH) | Trp 245 |
S | −80.14 | Ser 283 (NHCO) Tyr 489 (NH) | Trp 245, Tyr 489 | ||
3l (2-OCH3, 4-NO2) | 0.74 | R | −120.40 | Gly 279 (NHCO), Ser 289 (NHCO) Ser 289 (OCH3) | Trp 245, Tyr 489, His 600, Glu 359 (ion-pi) |
S | −89.15 | Ser 283 (NHCO) Tyr 489 (NH) | Trp 245, Tyr 282, Tyr 489, Tyr 493 (ion-pi) | ||
3m (2-OH, 5-NO2) | 0.59 | R | −127.01 | Ser 283 (NHCO), Tyr 489 (NH) Tyr 489 (OH) | Trp 245, Tyr 282, Tyr 489 |
S | −113.14 | Trp 245 (NH) Ser 283 (OH) | Trp 245, Glu 359 (ion-pi), His 600 (ion-pi) | ||
3n (4-OH) | 0.50 | R | −91.36 | Ser 280 (NHCO), Tyr 291 (OH) Glu 359 (OH) | Trp 245, Tyr 282, Tyr 489 |
S | −121.58 | Ser 280 (NHCO), Tyr 291 (OH) Glu 359 (OH) | Trp 245 |
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Venugopala, K.N.; Ramachandra, P.; Tratrat, C.; Gleiser, R.M.; Bhandary, S.; Chopra, D.; Morsy, M.A.; Aldhubiab, B.E.; Attimarad, M.; Nair, A.B.; et al. Larvicidal Activities of 2-Aryl-2,3-Dihydroquinazolin -4-ones against Malaria Vector Anopheles arabiensis, In Silico ADMET Prediction and Molecular Target Investigation. Molecules 2020, 25, 1316. https://doi.org/10.3390/molecules25061316
Venugopala KN, Ramachandra P, Tratrat C, Gleiser RM, Bhandary S, Chopra D, Morsy MA, Aldhubiab BE, Attimarad M, Nair AB, et al. Larvicidal Activities of 2-Aryl-2,3-Dihydroquinazolin -4-ones against Malaria Vector Anopheles arabiensis, In Silico ADMET Prediction and Molecular Target Investigation. Molecules. 2020; 25(6):1316. https://doi.org/10.3390/molecules25061316
Chicago/Turabian StyleVenugopala, Katharigatta N., Pushpalatha Ramachandra, Christophe Tratrat, Raquel M. Gleiser, Subhrajyoti Bhandary, Deepak Chopra, Mohamed A. Morsy, Bandar E. Aldhubiab, Mahesh Attimarad, Anroop B. Nair, and et al. 2020. "Larvicidal Activities of 2-Aryl-2,3-Dihydroquinazolin -4-ones against Malaria Vector Anopheles arabiensis, In Silico ADMET Prediction and Molecular Target Investigation" Molecules 25, no. 6: 1316. https://doi.org/10.3390/molecules25061316